Review ArticleAntiviral Nanodelivery Systems Current Trends inAcyclovir Administration

Haniza Hassan1 Siti Khadijah Adam1 Fauziah Othman1

Ahmad Fuad Shamsuddin23 and Rusliza Basir1

1Department of Human Anatomy Faculty of Medicine and Health Sciences Universiti Putra Malaysia (UPM)43400 Serdang Selangor Malaysia2Centre for Drug Delivery Research Faculty of Pharmacy Universiti Kebangsaan Malaysia Jalan Raja Muda Abdul Aziz50300 Kuala Lumpur Malaysia3Faculty of Pharmacy amp Health Sciences Universiti Kuala Lumpur Royal College of Medicine Perak No 3 Jalan Greentown30450 Ipoh Perak Malaysia

Correspondence should be addressed to Ahmad Fuad Shamsuddin drafsnagmailcom and Rusliza Basir ruslizaupmedumy

Received 4 April 2016 Revised 19 July 2016 Accepted 25 July 2016

Academic Editor Changyang Gong

Copyright copy 2016 Haniza Hassan et alThis 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

Poor bioavailability of acyclovir in the treatment of viral infections remains one of the major drug delivery concerns ofpharmaceutical manufacturers and researchers Nanoparticulate systems have been exploited with the aim of improving the currentpharmacological limitations of acyclovir administration In fact nanoparticles do offermany advantages especially in terms of theirphysicochemical stability and sustained-release properties Besides they are made of biocompatible materials which are nontoxicto cells Acyclovir has been a focus since the last decade as one of the low bioavailability drug models loaded in various types ofnewly synthesized drug delivery vehicles In this review compositions and formulations of nanosized acyclovir particles as well astheir stability and pharmacokinetic profile are discussed in further detail

1 Introduction

Acyclovir is an antiviral drug that is primarily used for thetreatment of HSV (herpes simplex virus) infection as wellas infections due to varicella zoster and herpes zoster It hashigher activity towards both HSV-1 and HSV-2 as comparedto the latter viral infections Acyclovir remains the drug ofchoice for prophylaxis and treatment of HSV infection andis available in numerous forms such as tablet suspensionintravenous injection and ophthalmic ointment (Table 1)

Acyclovir is a guanosine analogue with a functionalaliphatic group that is present on the side chain It obstructsthe virus replication process by competitively inhibiting theviral DNA formationThis is achieved through selective bind-ing of HSV-thymidine kinase Acyclovir is then converted bythe viral thymidine kinase to acycloguanosine monophos-phate (acyclo-GMP) followed by phosphorylation by thecellular kinase into an active triphosphate form acycloguano-sine triphosphate (acyclo-GTP) The acyclo-GTP which has

greater affinity for the viral DNA polymerase as compared tocellular polymerase functions as a substrate that binds withand is incorporated into viral DNA Eventually this resultsin premature chain termination as acyclo-GTP resembles thenucleotides but without the hydroxyl group in the 31015840 position[1ndash3] The absence of this hydroxyl group means that furthernucleotides cannot be added to the strand for elongation andhence the incomplete DNA strand is terminated (Figure 1)As a consequence the replication rate is slowed down andfurther provides ample time for the immune response tointervene

Acyclovir is poorly soluble in water contributing to only20 of the total free drug in the body It is also rapidlycleared from the system where the half-life of the drug isreported to be three hours Unchanged acyclovir and itsmetabolite 9-carboxy-methoxymethylguanine can be foundin the urine as kidneys are the major organs for the drugsrsquoelimination [4] By virtue of this acyclovir does not havesufficient bioavailability accounting for only up to 30 in

Hindawi Publishing CorporationJournal of NanomaterialsVolume 2016 Article ID 4591634 8 pageshttpdxdoiorg10115520164591634

2 Journal of Nanomaterials

Table 1 Route of administration of acyclovir and the disadvantages

Route of administration Dose Disadvantages

Oral 1000mg per day (tablet and suspension) Low oral bioavailability high-dose related side effects thatis nausea headache and diarrhoea [8 15]

Intravenous injection 100mgkg Nephrotoxicity renal failure and thrombophlebitis [21 28]

Topicaltransdermal 5 ww topical ointment 5 times daily Difficulty in penetrating epidermal layer rapid clearance[29]

Ocular 3 ww ophthalmic ointment 5 times a day Poor ocular bioavailability [30]

Acyclovir + ATP

HSV-thymidinekinase

Acycloguanosine monophosphate

Cellularkinase

HSV

Acyclovir triphosphate binds with and is incorporated into viral DNA

Inhibition of viral DNA synthesis and viral replication process

DNA polymerase

Acycloguanosine triphosphate

Figure 1 Schematic mechanism of action of acyclovir in inhibiting viral DNA synthesis

immunocompetent patient with no previous history of renalproblem or complication [5ndash7] Nonetheless this percentagevaries from one individual to another and it is subjectedto the individual pharmacokinetic profile of patients Poorbioavailability of acyclovir has led to ineffective therapyA simplistic approach to overcome this is by prescribingacyclovir in high oral doses that is 200mg tablet five timesdaily for ten consecutive days or even higher doses of 400mgif required Higher doses are prescribed by physicians toobtain higher serum concentration hence achieving itsdesired therapeutic effects [8ndash10] Nonetheless the use ofhigher drug doses may lead to unwarranted adverse effects

New or enhanced techniques and formulations areneeded to improve the efficacy of the current antiviral therapyusing acyclovir Less frequent dosing lower dose of acyclovirused and sustained-release mechanisms are approachesutilised to improve therapy and reduce the possibility ofgetting side effects related to high dose of drug consumedThis can very much improve patient compliance to antiviraltherapy using acyclovir Research in the nanoparticulatesystem as drug carriers has received intense and worldwideattention This novel system is seen to be the next step inimproving antiviral therapyNanoparticles have been selectedto deliver drugs effectively with minimal to no toxicity effects[11ndash13] Usage of nanoparticles in medicine has broughtforward more options in developing future drug as well asimproving the currently available formulations which areinundated with pharmacological limitations

Nanosized drug delivery vehicle has been expected tofulfil the main pharmacokinetic objectives that is improvingacyclovirrsquos solubility and hence absorption and oral bioavail-ability Moreover it is believed that nanosized acyclovir maypotentially improve the drugrsquos dissolution profile thus over-coming its pharmacokinetic drawback For these reasonsvarious types of nanosized drug delivery vehicles have beenstudied formulated and prepared by using differentmethodsto encapsulate and deliver acyclovir via different routes ofadministration This drug delivery system includes syntheticand natural products which are safe for consumers Theseproducts are made of biologically inert and physiologicallycompatible materials Besides most nanocarriers are formu-lated to be biodegradable which is helpful in avoiding toxicityAcyclovir nanocarriers are discussed in detail with respect totheir route of administration

2 Oral Delivery

The purpose of high doses of oral acyclovir (typically a200mg tablet taken 5 times a day for 10 days) prescribedto patients is to achieve the desired acyclovir concentrationcirculated in plasma thus attaining significant pharmaco-logical effect of acyclovir Notably oral delivery is the mostpreferred route of administration However patient compli-ance is compromised if acyclovir oral tablets are requiredto be taken five times daily On top of that the patient isexposed to side effects related to high doses of acyclovir

Journal of Nanomaterials 3

administration Some of the common side effects of orallydelivered acyclovir are nausea vomiting diarrhoea andheadache [8] In order to obtain therapeutic effect of as wellas enhancing compliance and minimising its dose relatedside effects various techniques and methods for delivery ofacyclovir have been developed

A lipid nanoemulsion system has been designed andintroduced to entrap acyclovirThis emulsion system is madeup of liquid lipids which are dispersed in water and stabilizedby emulsifier andor surfactant that coat the nanosizedlipid droplets Emulsifiers or surfactants are used to reducethe interfacial tension of lipid droplets with the aqueousphase (water) Surfactant and emuslifiers are added in theformulation to avoid droplets collision in order to maintainthe desired droplet size [14] Although the emulsifying tech-nique is quite an antiquated drug preparation technique themodern technology has adapted this method to a level whereit stands together with other newer drug delivery formsMoreover an improvement in drug solubility will definitelyhave a positive impact on the drug bioavailability

Nanoemulsion systems for oral acyclovir delivery havebeen shown to improve acyclovir oral bioavailability in ratswhen compared with the commercially available plain drugeither in tablet form or in solutions More importantly theparticles produced were within the nanometric size rangingfrom20 nm to 40 nmwith gooddrug entrapment and loadingcapacity [15 16] In addition liquid nanoemulsion developedshowed longer blood circulation time when compared withplain drug solution In contrast it was reported that the self-microemulsifying drug delivery system which was made upof 30 glycerol 9 sunflower oil and 60 tween 60 did notexhibit a sustained-release profile Also the half-life (11990512) wasreported to be about 25 to 3 hours which was similar to thepure drug solution [15] These studies showed that types andratio of the oil to surfactant (optimized using pseudoternaryphase diagram) used in formulating the nanoemulsion playeda major role in determining the sustained-release character-istic of the nanoemulsions constructed

More recently an in vitro drug release study of acyclovir-loaded Eudragi RLPO nanoparticles showed sustained drugrelease property for over a period of 24 hours Howeverthe use of Eudragi RLPO and a stabilizer Pluronic F68might not be a good combination for formulation of oraldrug delivery vehicle due to the fact that range of particlesize produced was large between 82 and 532 nm The drugentrapment efficiency was reported to be moderate at about53ndash79 [17] Thus the composition and the ratio of bothsurfactant and polymer used in the formulation directlyinfluenced the drug entrapment efficiency and its particlesizes as well as the polydispersity index In addition largesizes and high polydispersity index particles are indicators ofinstability of a formulation and are benchmarked to estimatethe nanoparticlersquos shelf-life storage condition

A stability test is one of the most crucial steps indeveloping drug carrier Usually the stability test of a newlyformulated drug is an indicator of the product performancesover time and an important criterion for future drug com-mercialization The shelf-life stability of the nanoemulsionformulation is an interesting area to study as some of the

emulsions prepared had been said to face instability problemsthat include separation and sedimentation of the preparedformulation Storage at room temperature for more than6 months would cause the prepared emulsion containingacyclovir to change in its globule size significantly Drugburstleakage has also been reported despite its good entrap-ment efficiency oral bioavailability and prolonged releasecharacteristic [18] However the system was stable if it waskept in controlled temperature (4∘C) [18 19] Thus furtherinvestigation into the compositions as well as the types oflipid used would give insightful and clearer perspective of theoral drug delivery system proposed

3 Systemic Blood Delivery(Intravenous (IV) Injections)

Numerous attempts have been made by scientists and re-searchers to develop acyclovir nanocarrier for IV injectionIn general bolus IV injection is only given to patients if veryhigh doses of acyclovir are required that is 100mgkg andorwhen serious cases of HSV infection are encountered such asherpes simplex encephalitis [20]

However delivery of acyclovir via IV injection wouldcause thrombophlebitis at the injection area Also high dosesof acyclovir could cause deposition of acyclovir crystals in thekidney especially if acyclovir is given via bolus IV injectionwhere themaximumsolubility is reachedThis eventmay leadto intratubular renal damage and hence renal failure [21ndash23]This is one of the common side effects if acyclovir dose is notadjusted or proper hydration is not given [24]

Novel IV stealthy nanoparticles using polylactic cogly-colic acid (PLGA) have been developed to address theinherent issue of poor acyclovir bioavailability The objectiveof this new system is to increase its mean residence time andplasma half-life The PLGA nanovehicles have been provento extend circulation time (longer mean residence time) foracyclovir that is up to 48 hours when compared to its control(plain drug solution) Studies have also shown that spherical-shaped PLGA nanoparticles have relatively good percentageof drug entrapment where more than 60 of drug addedwas entrapped in this carrier system Acyclovir in PLGAnanocarrier yielded a reasonable particle size ranging from200 nm to 300 nm [25 26]

A study in the use of acyclovir PLGA nanoparticles inrats has revealed a much improved acyclovir biodistributionin which the concentration of acyclovir PLGA nanoparticleswas highest in hepatocytes compared to other organs (iekidney and lungs) after an intravenous injection of the drugwas given through the tail vein [26] This is an exampleof a successful targeted drug delivery with prolonged andcontinuous drug release at the site-specific organ most likelycontributed by the types of drug carriers that interactedwithbound to the surrounding cell in this case hepatocytesAs acyclovir is also a useful therapeutic agent in treatingpatients with life-threatening infectious liver disease (eghepatitis B) the study provides promising evidence of util-ising this delivery system to carry acyclovir into the body

Self-assembled nanoparticles (SAN) formulated fromacyclovir lipid derivative (SGSA) have been claimed to be

4 Journal of Nanomaterials

stable during storage at room temperature SAN maintainedits particle size of 832 nm up to one year of storage andno particles aggregation was observed Further stability testson prepared SAN which included high speed centrifugation(up to 8000 rpm) with addition of selected additives haveshown that SGSA did not show any significant differencewhen compared with the control group However SGSA wasreported to have a short elimination time (7 hours) withcells toxicity observed This is an indication of a shorter resi-dencecirculation time of acyclovir in blood and cytotoxicityof the nanoparticles should be subjected to close scrutiny infuture research [27]

Factors such as composition and compatibility of eachcomponent used in the formulation and methods utilised inthe production process may impact the physical profiles ofthe resultant product prepared These factors may affect thesize stability and pharmacokinetic and pharmacodynamiccharacteristics of the nanoparticles formed Enhanced tech-nique and improved formulations to deliver acyclovir via IVinjection continue to attract interest from researchers andfurther investigations would be worthy of note

4 Topical and Transdermal Applications

Skin lesion and blisters due to infection of HSV can betreated with the application of acyclovir in the form of topicalointment or transdermal cream Topical and transdermalformulations act as vehicles for antiviral agents besidesrendering protective layer to prevent further virus entry andspread from a particular site of infectionThese formulationsalso improve the healing time of cold sores and blisters asthe application is localised at the site of infection Howeveracyclovir ointment has been reported to have only moderateefficacy depending on the severity of the infection and theclinical condition of patientsMoreover frequent applicationsof acyclovir topical creamare required to attain its therapeuticeffect [31 32] Also it has been reported that acyclovir creamand ointment have difficulties in penetrating the epidermallayer of the skin [31] Due to slow absorption of the drugat the site of application research into new and improvedformulations for acyclovir topical ointment has receivedsignificant attention

Additionally nanoemulsion and to an extent microemul-sion-based topical formulations have been developed fortreatment of cutaneous herpes infection The applications ofthese acyclovir formulations exhibited good skin permeationprofile and resulted in HSV-1 suppression at the site ofinfection [33 34] A study on the effect of microemulsion-based topical formulations of acyclovir for the treatment ofcutaneous herpetic infections showed a positive improve-ment where no herpetic skin lesion was observed after oneweek of treatment [34] In this study 25 transcutol (ethoxy-diglycol) microemulsion containing 075mg of acyclovir wasapplied once daily to female Balbc mice at 24 hours afterinfection and compared to its control group Furthermorethe formulations were found to be stable when kept on shelfat a room temperature of 25∘C for up to 45 days [34]

Although further investigations are required to closelyscrutinize its antiviral effect a study has confirmed that

application of acyclovir emulsion for treatment of skin HSVinfection enhanced the healing time due to improvementof its skin permeation profile Schwarz and colleage havealso postulated that acyclovir nanoemulsions formulationsusing natural sugar surfactant and Solutol HS 15 couldbe a suitable candidate for topical acyclovir delivery thatshould be developed as future drug vehicles [33] Thesefindings suggested that drug carrier should not only possessgood physicochemical stability and drug loading capacitybut also be made of skin-friendly materials and be capableof penetrating the skin barrier that allows interaction withthe surrounding cells ensuring sustained drug release to thetargeted area

Beside emulsions colloidal dispersion drug deliverysystem has also been exploited for dermal delivery ofacyclovir A detailed in vitro comparative study betweenethosomes and solid lipid nanoparticles (SLNs) as acyclovirdrug carriers reported improved drug encapsulation withcomparable ability to carry high amount of acyclovir Theethosomal system utilising phosphatidylcholine showed 94drug encapsulation which was 39 higher than tristearinsolid lipid nanoparticle These systems showed similar sizeof particles of 257 nm and 236 nm respectively Evaluationstudy on antiviral activity of both acyclovir formulationsin plaque reduction assay of infected Vero cells culturesproduced similar results when compared to control (plainacyclovir solution) [35] Thus it could be concluded thatboth formulations did not affect the efficacy of the drug Inaddition data obtained from an in vitro release kinetic studysuggested that ethosomes and SLNs have sustained-releasecharacteristic where continuous drug delivery of acyclovirwas observed This positive characteristic should be furtherexploited

Typically drug prepared in a form of gel using in situgelling system is suitable for topical administration as itoffers site-specific and targeted drug delivery Encapsulatedacyclovir in polymer nanoparticles dispersion gelling sys-tem such as Pluronic F127 is not subjected to topical andtransdermal application only but also nasal and vaginaldeliveries Ramyadevi and Sandhya reported that regardlessof its wide range of particles size distribution (between 68 nmand 1281 nm) the system exhibited reasonable drug loadingcapacity (between 30 and 60) with up to 8 hours ofsustained-release profile In fact both characteristics hadfulfilled the main objective of the study a modified dosageform of acyclovir for delivery to the skin [36] Furtherinvestigations on its in vivo bioavailability would be worthy ofadditional information for the system developed Thereforeintense research and work progress in this area are requiredthat is the toxicity and the stability of the formulationin order to improve the current findings for better andpromising drug delivery methods and preparations

5 Ocular Delivery

Besides topical ointment acyclovir has also been targeted forits ocular delivery Ocular HSV infection occurs when HSVtype 1 infects the sensory neurons of the eye To date herpetickeratitis is one of the most common infectious eye diseases

Journal of Nanomaterials 5

associated with HSV [37] Prolonged herpes keratitis due tolack of treatment or recurrent infection of HSV at the samearea of the cornea would cause dendritic ulcer Eventuallythis event may cause visual impairment or worse blindnessdue to scarring and damage formed in the infected area[38 39]

Acyclovir is not prescribed to patients in the form of eyedrops because of its poor ocular bioavailability and thera-peutic efficacy due to low solubility in water On top of thatdevelopment of drug for delivery to the eye is very challeng-ing There are few factors that need to be taken into consid-eration when designing drug for ocular delivery Eyes havetheir own physical and biological protective mechanismsthat protect them from foreign substances including drugsFor example blinking and tears will reduce andor removeophthalmic drug solution from the conjunctiva There-fore it is quite difficult to get the actual dose of drugto reach the targeted tissue area hence resulting in lowocular drug absorption [40] Treatment of ocular HSV inimmunocompetent patients is prescription of oral acyclovir(800mg daily) andor continuous application of 3 acy-clovir ophthalmic ointment to the cornea area five timesdaily [30 41]

In the last decade a pioneer studywas conducted to inves-tigate the potential of liposome as acyclovir delivery vehicleLiposome offers great advantages as a colloidal drug carrierit is made of biodegradable materials and is nontoxic to cellsBy virtue of that nanosized liposomesmade of phosphatidyl-choline-cholesterol-dimethyl dioctadecyl had been devel-oped to transport acyclovir to the eyes Characteristics ofthe liposomes prepared from different procedures and mem-brane charges were evaluated Data of the study suggestedthat only charged membranes (either positively or negativelycharged liposomes) could interact with acyclovir Negativelycharged liposomes showed the highest drug entrapment effi-ciency when compared with neutral and positively chargedliposomes which could be due to greater aqueous phaseentrapmentwithin the corewhere acyclovir was placedHow-ever only positively charged liposomes showed enhancedocular acyclovir bioavailability in the aqueous humor Thiscould be due to corneal permeability adjustment made byliposomes which allows more drug to enter the cornea area[42]

In agreement with previous study positively chargedliposome was also reported to be bound to and coated onthe corneal surface and enhanced the absorption of acyclovirin the cornea Also longer acyclovir residence time of thepositively charged liposomes was observed in the aqueoushumor of the rabbits due to corneal adhesion as comparedto the commercially available acyclovir ointment [43 44] Insummary a few factors have been discovered to influence theimprovement of acyclovir-liposomes ophthalmic deliverywhich includes rate of corneal permeation and surface chargeof the fabricated liposomes such that it binds to and coats thenegatively charged corneal surface

Besides liposomes poly(ethylene glycol)-co-cyclic acetal(PECA) and polylactic acid (PLA) nanospheres coated withpolyethylene glycol (PEG) with average diameter of 200 nmcould also be a good and suitable drug vehicle for acyclovir

Acyclovir-loaded PECA and PLA nanospheres have demon-strated sustained-release property with mean residence timeof up to 6 hours [45 46] In vivoDraize tests were conductedand findings suggested that nanospheres made from bothtypes of polymer were well tolerated with no eye inflam-mation observed Thus acyclovir-loaded nanospheres wereconsidered safe for ocular use since changes were not seen inthe rabbitrsquos eyes

Acyclovir-loaded PEG coated nanospheres had shown asignificant increase of acyclovir concentration in the aqueoushumor when compared with acyclovir solution These couldhave resulted from higher drug loading capacity and betterocular mucoadhesion of the formulated nanospheres Gooddrug loading capacity and high ocular bioavailability areindication of a successful trial of acyclovir encapsulationfor its ocular delivery Data of the studies suggested thatdrug entrapment efficiency is subjected to environmentand preparation conditions (ie pH and temperature) andtypes and molecular weight of the surfactant and polymerused in the formulation In addition the compositionconcentration and ratio of surfactant and polymer usedin the formulation might influence the physicochemicalproperties of lipid nanoparticles and the ocular tolerabil-ity [47ndash49] Further investigation to test the nanospheresrsquoshelf-life stability will be beneficial for future ocular drugdelivery development

More recently solid lipid nanoparticles have been intro-duced to be a carrier system to deliver poorly water-soluble andor hydrophobic drug It offers many advan-tages over the older colloidal drug delivery systems whichinclude biocompatibility biodegradability and beingmade ofsafenontoxic materials [50 51]Thus as a stable drug carriersolid lipid nanoparticles have been proposed to be a drugvehicle for ophthalmic delivery of acyclovir Acyclovir hasbeen successfully incorporated into solid lipid nanoparticlesmade from glyceryl dibehanate Compritol 888 ATO usingthe modified hot-oil-in-water microemulsion techniqueThemorphology stability and other characteristics of the newlysynthesized nanoparticles were determined before they weretested in excised bovine cornea It was reported that thenegatively charged nanoparticle displayed poor permeationthrough cornea although it exhibited sustained-release profileto supply acyclovir for a longer period of timeHence in orderto overcome the drawback solid lipid nanoparticles havebeen physically converted to nanostructured lipid carriers(400ndash777 nm in diameter) with good drug loading capacitycharacteristic [52]

Besides having good drug entrapment efficiency of up to90 the nanostructured lipid carrier system also enhancedthe acyclovir corneal permeation This has caused an incre-ment of acyclovir cell uptake and its corneal bioavailabilityApart from that chitosan-coated nanostructured lipid carrieralso improved the antiviral efficacy of acyclovir by 35-fold after 24-hour exposure in the cornea of albino rabbitswhen compared with the commercial acyclovir ophthalmicointment available in the market [52 53] The physicochem-ical properties and structures of the formulated solid lipidnanoparticles (ie where acyclovir is loaded in the system)directly influence the bioavailability of acyclovir and rate of

6 Journal of Nanomaterials

corneal permeation as well as its stability These are amongthe important measures for a successful development ofophthalmic drug delivery

6 Conclusion

The development of nanosized drug delivery system forantiviral drugs specifically acyclovir has shown a very goodprogress and high potential to become successful for futurebenefits The delivery of acyclovir through different routes ofadministration in different forms of formulations (ie tabletssuspension and ointment) is substantial in treating patientswith HSV where infection can be mild to one individualbut severe to others depending on their health status Yeteach route of administration has its own disadvantages andside effects Alternative acyclovir delivery system is indeed avery good research area to explore The forthcoming com-mercialization of the end product will be the most excitingpart especially to the pharmaceutical industryNonetheless afew fundamental steps have to be carefully studied before theformulation can be commercializedMoreover it is necessarythat the selection of delivery vehicle for acyclovir be testedvia in vitro and in vivo studies Its optimized therapeuticefficacy and toxicity data can be attained as well as its stabilitytest as a prerequisite for clinical trials Although furtherresearch and studies are required to be performed the currentand up-to-date data from various studies conducted utilisingdifferent methods technology and resources have gainedworldwide attention and thus have contributed importantinformation in this area of research In fact the proposedvehicles have the potential to be commercialized to suitthe current needs for antiviral delivery to overcome itspharmacokinetic drawbacks Research in the nanodeliverysystem for acyclovir will add on to the latest knowledgeand improve our understanding in drug discovery as well asdelivery systems The new technology and system proposedwill not only benefit antiviral drug delivery but also benefitother marketed drugs with similar delivery problems

Competing Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] G B Elion ldquoThe biochemistry and mechanism of action ofacyclovirrdquo Journal of Antimicrobial Chemotherapy vol 12 pp9ndash17 1983

[2] G B Elion ldquoAcyclovir discovery mechanism of action andselectivityrdquo Journal of Medical Virology vol 1 supplement 1 pp2ndash6 1993

[3] J Piret and G Boivin ldquoResistance of herpes simplex viruses tonucleoside analogues mechanisms prevalence and manage-mentrdquo Antimicrobial Agents and Chemotherapy vol 55 no 2pp 459ndash472 2011

[4] J P Smith S Weller B Johnson J Nicotera J M Luther andD W Haas ldquoPharmacokinetics of acyclovir and its metabolites

in cerebrospinal fluid and systemic circulation after adminis-tration of high-dose valacyclovir in subjects with normal andimpaired renal functionrdquo Antimicrobial Agents and Chemother-apy vol 54 no 3 pp 1146ndash1151 2010

[5] R J Whitley M R Blum N Barton and P DeMiranda ldquoPhar-macokinetics of acyclovir in humans following intravenousadministration A model for the development of parenteralantiviralsrdquoThe American Journal of Medicine vol 73 no 1 pp165ndash171 1982

[6] J-M Poirier N Radembino and P Jaillon ldquoDetermination ofacyclovir in plasma by solid-phase extraction and column liquidchromatographyrdquo Therapeutic Drug Monitoring vol 21 no 1pp 129ndash133 1999

[7] M Kubbinga M A Nguyen P Staubach S Teerenstra and PLangguth ldquoThe influence of chitosan on the oral bioavailabilityof acyclovirmdasha comparative bioavailability study in humansrdquoPharmaceutical Research vol 32 no 7 pp 2241ndash2249 2015

[8] A Wald J Benedetti G Davis M Remington C Winterand L Corey ldquoA randomized double-blind comparative trialcomparing high- and standard-dose oral acyclovir for first-episode genital herpes infectionsrdquo Antimicrobial Agents andChemotherapy vol 38 no 2 pp 174ndash176 1994

[9] Y J Bryson M Dillon M Lovett et al ldquoTreatment of firstepisodes of genital herpes simplex virus infection with oral acy-clovir A randomized double-blind controlled trial in normalsubjectsrdquoTheNew England Journal of Medicine vol 308 no 16pp 916ndash921 1983

[10] G W Raborn W T McGaw M Grace L D Tyrrell and SM Samuels ldquoOral acyclovir and herpes labialis a randomizeddouble-blind placebo-controlled studyrdquo The Journal of theAmerican Dental Association vol 115 no 1 pp 38ndash42 1987

[11] H Shirazi M Daneshpour S Kashanian and K OmidfarldquoSynthesis characterization and in vitro biocompatibility studyof AuTMCFe3O4 nanocomposites as a promising nontoxicsystem for biomedical applicationsrdquo Beilstein Journal of Nan-otechnology vol 6 no 1 pp 1677ndash1689 2015

[12] M B Chaudhari P P Desai P A Patel and V B PatravaleldquoSolid lipid nanoparticles of amphotericin B (AmbiOnp) invitro and in vivo assessment towards safe and effective oraltreatment modulerdquo Drug Delivery and Translational Researchvol 6 no 4 pp 354ndash364 2016

[13] Y Oh N Lee H W Kang and J Oh ldquoIn vitro study onapoptotic cell death by effective magnetic hyperthermia withchitosan-coated MnFe2O4rdquo Nanotechnology vol 27 no 11article 115101 2016

[14] B Sapra PThatai S Bhandari J SoodM Jindal andA TiwaryldquoA critical appraisal of microemulsions for drug deliverymdashpartIrdquoTherapeutic Delivery vol 4 no 12 pp 1547ndash1564 2013

[15] D Patel and K K Sawant ldquoOral bioavailability enhancementof acyclovir by self-microemulsifying drug delivery systems(SMEDDS)rdquo Drug Development and Industrial Pharmacy vol33 no 12 pp 1318ndash1326 2007

[16] P KGhosh R JMajithiyaM LUmrethia andR S RMurthyldquoDesign and development of microemulsion drug deliverysystem of acyclovir for improvement of oral bioavailabilityrdquoAAPS PharmSciTech vol 7 no 3 p 77 2006

[17] A Gandhi S Jana and K K Sen ldquoIn-vitro release of acyclovirloaded Eudragit RLPO nanoparticles for sustained drug deliv-eryrdquo International Journal of Biological Macromolecules vol 67pp 478ndash482 2014

[18] S Paul A Kumar P Yedurkar and K Sawant ldquoDesign anddevelopment of multiple emulsion for enhancement of oral

Journal of Nanomaterials 7

bioavailability of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 11 pp 1809ndash1817 2013

[19] B B Ghera F Perret Y Chevalier and H Parrot-LopezldquoNovel nanoparticles made from amphiphilic perfluoroalkyl120572-cyclodextrin derivatives preparation characterization andapplication to the transport of acyclovirrdquo International Journalof Pharmaceutics vol 375 no 1-2 pp 155ndash162 2009

[20] U Sili A Kaya A Mert et al ldquoHerpes simplex virus encephali-tis clinical manifestations diagnosis and outcome in 106 adultpatientsrdquo Journal of Clinical Virology vol 60 no 2 pp 112ndash1182014

[21] X Zhang Y Li H Zhou et al ldquoPlasma metabolic profilinganalysis of nephrotoxicity induced by acyclovir using metabo-nomics coupled with multivariate data analysisrdquo Journal ofPharmaceutical and Biomedical Analysis C vol 97 pp 151ndash1562014

[22] A Seedat and G Winnett ldquoAcyclovir-induced acute renalfailure and the importance of an expanding waist linerdquo BMJCase Reports 2012

[23] H Lu Y-J Han J-D Xu W-M Xing and J Chen ldquoPro-teomic characterization of acyclovir-induced nephrotoxicity ina mouse modelrdquo PLoS ONE vol 9 no 7 Article ID e1031852014

[24] R Fleischer and M Johnson ldquoAcyclovir nephrotoxicity a casereport highlighting the importance of prevention detectionand treatment of acyclovir-induced nephropathyrdquo Case Reportsin Medicine vol 2010 Article ID 602783 3 pages 2010

[25] A O Kamel G A S Awad A S Geneidi and N D MortadaldquoPreparation of intravenous stealthy acyclovir nanoparticleswith increased mean residence timerdquo AAPS PharmSciTech vol10 no 4 pp 1427ndash1436 2009

[26] S Gupta A Agarwal N K Gupta G Saraogi H Agrawal andG P Agrawal ldquoGalactose decorated PLGA nanoparticles forhepatic delivery of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 12 pp 1866ndash1873 2013

[27] Y Jin L Tong P Ai M Li and X Hou ldquoSelf-assembled drugdelivery systems 1 Properties and in vitroin vivo behaviorof acyclovir self-assembled nanoparticles (SAN)rdquo InternationalJournal of Pharmaceutics vol 309 no 1-2 pp 199ndash207 2006

[28] S Rao M J Abzug P Carosone-Link et al ldquoIntravenousacyclovir and renal dysfunction in children A Matched CaseControl Studyrdquo The Journal of Pediatrics vol 166 no 6 pp1462e4ndash1468e4 2015

[29] A B Nair ldquoQuantification of uptake and clearance of acyclovirin skin layersrdquo Antiviral Therapy vol 21 no 1 pp 17ndash25 2015

[30] S Ghosh V Jhanji E Lamoureux H R Taylor and R BVajpayee ldquoAcyclovir therapy in prevention of recurrent herpetickeratitis following penetrating keratoplastyrdquo American Journalof Ophthalmology vol 145 no 2 pp 198ndash202 2008

[31] G E Parry P Dunn V P Shah and L K Pershing ldquoAcyclovirbioavailability in human skinrdquo The Journal of InvestigativeDermatology vol 98 no 6 pp 856ndash863 1992

[32] S A Qureshi M Jiang K K Midha and J P Skelly ldquoInvitro evaluation of percutaneous absorption of an acyclovirproduct using intact and tape-stripped human skinrdquo Journal ofPharmacy amp Pharmaceutical Sciences vol 1 no 3 pp 102ndash1071998

[33] J C Schwarz V Klang S Karall D Mahrhauser G P Reschand C Valenta ldquoOptimisation of multiple WOW nanoemul-sions for dermal delivery of aciclovirrdquo International Journal ofPharmaceutics vol 435 no 1 pp 69ndash75 2012

[34] G Shishu S Rajan and Kamalpreet ldquoDevelopment of novelmicroemulsion-based topical formulations of acyclovir for thetreatment of cutaneous herpetic infectionsrdquo AAPS Pharm-SciTech vol 10 no 2 pp 559ndash565 2009

[35] R Cortesi L Ravani E Menegatti M Drechsler and EEsposito ldquoColloidal dispersions for the delivery of acyclovir AComparative Studyrdquo Indian Journal of Pharmaceutical Sciencesvol 73 no 6 pp 687ndash693 2011

[36] D Ramyadevi and P Sandhya ldquoDual sustained release deliverysystem for multiple route therapy of an antiviral drugrdquo DrugDelivery vol 21 no 4 pp 276ndash292 2014

[37] E Miserocchi G Fogliato I Bianchi F Bandello and GModorati ldquoClinical features of ocular herpetic infection in anItalian referral centerrdquo Cornea vol 33 no 6 pp 565ndash570 2014

[38] S Burrel D Boutolleau G Azar et al ldquoPhenotypic andgenotypic characterization of acyclovir-resistant corneal HSV-1 isolates from immunocompetent patients with recurrentherpetic keratitisrdquo Journal of Clinical Virology vol 58 no 1 pp321ndash324 2013

[39] O Alekseev A H Tran and J Azizkhan-Clifford ldquoEx vivoorganotypic corneal model of acute epithelial herpes simplexvirus type I infectionrdquo Journal of Visualized Experiments no 69Article ID e3631 2012

[40] C Bucolo F Drago and S Salomone ldquoOcular drug deliverya clue from nanotechnologyrdquo Frontiers in Pharmacology vol 3article 188 2012

[41] D D Garcia Q Farjo D C Musch and A Sugar ldquoEffect ofprophylactic oral acyclovir after penetrating keratoplasty forherpes simplex keratitisrdquo Cornea vol 26 no 8 pp 930ndash9342007

[42] M Fresta A M Panico C Bucolo C Giannavola and GPuglisi ldquoCharacterization and in-vivo ocular absorption ofliposome-encapsulated acyclovirrdquoThe Journal of Pharmacy andPharmacology vol 51 no 5 pp 565ndash576 1999

[43] S L Law K J Huang and C H Chiang ldquoAcyclovir-containingliposomes for potential ocular delivery corneal penetration andabsorptionrdquo Journal of Controlled Release vol 63 no 1-2 pp135ndash140 2000

[44] P Chetoni S Rossi S Burgalassi D Monti S Mariotti and MF Saettone ldquoComparison of liposome-encapsulated acyclovirwith acyclovir ointment ocular pharmacokinetics in rabbitsrdquoJournal of Ocular Pharmacology andTherapeutics vol 20 no 2pp 169ndash177 2004

[45] C Giannavola C Bucolo A Maltese et al ldquoInfluence ofpreparation conditions on acyclovir-loaded poly-dl-lactic acidnanospheres and effect of PEG coating on ocular drug bioavail-abilityrdquo Pharmaceutical Research vol 20 no 4 pp 584ndash5902003

[46] M Fresta G Fontana C Bucolo G Cavallaro G Giammonaand G Puglisi ldquoOcular tolerability and in vivo bioavailability ofpoly(ethylene glycol) (PEG)-coated polyethyl-2-cyanoacrylatenanosphere-encapsulated acyclovirrdquo Journal of PharmaceuticalSciences vol 90 no 3 pp 288ndash297 2001

[47] A Leonardi C Bucolo G L Romano et al ldquoInfluence ofdifferent surfactants on the technological properties and in vivoocular tolerability of lipid nanoparticlesrdquo International Journalof Pharmaceutics vol 470 no 1-2 pp 133ndash140 2014

[48] R Pignatello C Bucolo and G Puglisi ldquoOcular tolerability ofEudragit RS100 and RL100 nanosuspensions as carriers forophthalmic controlled drug deliveryrdquo Journal of PharmaceuticalSciences vol 91 no 12 pp 2636ndash2641 2002

8 Journal of Nanomaterials

[49] C Bucolo A Maltese F Maugeri B Busa G Puglisi and RPignatello ldquoEudragit RL100 nanoparticle system for the oph-thalmic delivery of cloricromenerdquoThe Journal of Pharmacy andPharmacology vol 56 no 7 pp 841ndash846 2004

[50] S Misra K Chopra V R Sinha and B Medhi ldquoGalantamine-loaded solidndashlipid nanoparticles for enhanced brain deliverypreparation characterization in vitro and in vivo evaluationsrdquoDrug Delivery vol 23 no 4 pp 1434ndash1443 2016

[51] J Albuquerque C C Moura B Sarmento and S ReisldquoSolid lipid nanoparticles a potential multifunctional approachtowards rheumatoid arthritis theranosticsrdquo Molecules vol 20no 6 pp 11103ndash11118 2015

[52] A Seyfoddin and R Al-Kassas ldquoDevelopment of solid lipidnanoparticles and nanostructured lipid carriers for improvingocular delivery of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 4 pp 508ndash519 2013

[53] A Seyfoddin T Sherwin D V Patel et al ldquoEx vivo and in vivoevaluation of chitosan coated nanostructured lipid carriers forocular delivery of acyclovirrdquo Current Drug Delivery In press

Submit your manuscripts athttpwwwhindawicom

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CorrosionInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Polymer ScienceInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CeramicsJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CompositesJournal of

NanoparticlesJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Biomaterials

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

NanoscienceJournal of

TextilesHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Journal of

NanotechnologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

CrystallographyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CoatingsJournal of

Advances in

Materials Science and EngineeringHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Smart Materials Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MetallurgyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

MaterialsJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Nano

materials

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal ofNanomaterials

2 Journal of Nanomaterials

Table 1 Route of administration of acyclovir and the disadvantages

Route of administration Dose Disadvantages

Oral 1000mg per day (tablet and suspension) Low oral bioavailability high-dose related side effects thatis nausea headache and diarrhoea [8 15]

Intravenous injection 100mgkg Nephrotoxicity renal failure and thrombophlebitis [21 28]

Topicaltransdermal 5 ww topical ointment 5 times daily Difficulty in penetrating epidermal layer rapid clearance[29]

Ocular 3 ww ophthalmic ointment 5 times a day Poor ocular bioavailability [30]

Acyclovir + ATP

HSV-thymidinekinase

Acycloguanosine monophosphate

Cellularkinase

HSV

Acyclovir triphosphate binds with and is incorporated into viral DNA

Inhibition of viral DNA synthesis and viral replication process

DNA polymerase

Acycloguanosine triphosphate

Figure 1 Schematic mechanism of action of acyclovir in inhibiting viral DNA synthesis

immunocompetent patient with no previous history of renalproblem or complication [5ndash7] Nonetheless this percentagevaries from one individual to another and it is subjectedto the individual pharmacokinetic profile of patients Poorbioavailability of acyclovir has led to ineffective therapyA simplistic approach to overcome this is by prescribingacyclovir in high oral doses that is 200mg tablet five timesdaily for ten consecutive days or even higher doses of 400mgif required Higher doses are prescribed by physicians toobtain higher serum concentration hence achieving itsdesired therapeutic effects [8ndash10] Nonetheless the use ofhigher drug doses may lead to unwarranted adverse effects

New or enhanced techniques and formulations areneeded to improve the efficacy of the current antiviral therapyusing acyclovir Less frequent dosing lower dose of acyclovirused and sustained-release mechanisms are approachesutilised to improve therapy and reduce the possibility ofgetting side effects related to high dose of drug consumedThis can very much improve patient compliance to antiviraltherapy using acyclovir Research in the nanoparticulatesystem as drug carriers has received intense and worldwideattention This novel system is seen to be the next step inimproving antiviral therapyNanoparticles have been selectedto deliver drugs effectively with minimal to no toxicity effects[11ndash13] Usage of nanoparticles in medicine has broughtforward more options in developing future drug as well asimproving the currently available formulations which areinundated with pharmacological limitations

Nanosized drug delivery vehicle has been expected tofulfil the main pharmacokinetic objectives that is improvingacyclovirrsquos solubility and hence absorption and oral bioavail-ability Moreover it is believed that nanosized acyclovir maypotentially improve the drugrsquos dissolution profile thus over-coming its pharmacokinetic drawback For these reasonsvarious types of nanosized drug delivery vehicles have beenstudied formulated and prepared by using differentmethodsto encapsulate and deliver acyclovir via different routes ofadministration This drug delivery system includes syntheticand natural products which are safe for consumers Theseproducts are made of biologically inert and physiologicallycompatible materials Besides most nanocarriers are formu-lated to be biodegradable which is helpful in avoiding toxicityAcyclovir nanocarriers are discussed in detail with respect totheir route of administration

2 Oral Delivery

The purpose of high doses of oral acyclovir (typically a200mg tablet taken 5 times a day for 10 days) prescribedto patients is to achieve the desired acyclovir concentrationcirculated in plasma thus attaining significant pharmaco-logical effect of acyclovir Notably oral delivery is the mostpreferred route of administration However patient compli-ance is compromised if acyclovir oral tablets are requiredto be taken five times daily On top of that the patient isexposed to side effects related to high doses of acyclovir

Journal of Nanomaterials 3

administration Some of the common side effects of orallydelivered acyclovir are nausea vomiting diarrhoea andheadache [8] In order to obtain therapeutic effect of as wellas enhancing compliance and minimising its dose relatedside effects various techniques and methods for delivery ofacyclovir have been developed

A lipid nanoemulsion system has been designed andintroduced to entrap acyclovirThis emulsion system is madeup of liquid lipids which are dispersed in water and stabilizedby emulsifier andor surfactant that coat the nanosizedlipid droplets Emulsifiers or surfactants are used to reducethe interfacial tension of lipid droplets with the aqueousphase (water) Surfactant and emuslifiers are added in theformulation to avoid droplets collision in order to maintainthe desired droplet size [14] Although the emulsifying tech-nique is quite an antiquated drug preparation technique themodern technology has adapted this method to a level whereit stands together with other newer drug delivery formsMoreover an improvement in drug solubility will definitelyhave a positive impact on the drug bioavailability

Nanoemulsion systems for oral acyclovir delivery havebeen shown to improve acyclovir oral bioavailability in ratswhen compared with the commercially available plain drugeither in tablet form or in solutions More importantly theparticles produced were within the nanometric size rangingfrom20 nm to 40 nmwith gooddrug entrapment and loadingcapacity [15 16] In addition liquid nanoemulsion developedshowed longer blood circulation time when compared withplain drug solution In contrast it was reported that the self-microemulsifying drug delivery system which was made upof 30 glycerol 9 sunflower oil and 60 tween 60 did notexhibit a sustained-release profile Also the half-life (11990512) wasreported to be about 25 to 3 hours which was similar to thepure drug solution [15] These studies showed that types andratio of the oil to surfactant (optimized using pseudoternaryphase diagram) used in formulating the nanoemulsion playeda major role in determining the sustained-release character-istic of the nanoemulsions constructed

More recently an in vitro drug release study of acyclovir-loaded Eudragi RLPO nanoparticles showed sustained drugrelease property for over a period of 24 hours Howeverthe use of Eudragi RLPO and a stabilizer Pluronic F68might not be a good combination for formulation of oraldrug delivery vehicle due to the fact that range of particlesize produced was large between 82 and 532 nm The drugentrapment efficiency was reported to be moderate at about53ndash79 [17] Thus the composition and the ratio of bothsurfactant and polymer used in the formulation directlyinfluenced the drug entrapment efficiency and its particlesizes as well as the polydispersity index In addition largesizes and high polydispersity index particles are indicators ofinstability of a formulation and are benchmarked to estimatethe nanoparticlersquos shelf-life storage condition

A stability test is one of the most crucial steps indeveloping drug carrier Usually the stability test of a newlyformulated drug is an indicator of the product performancesover time and an important criterion for future drug com-mercialization The shelf-life stability of the nanoemulsionformulation is an interesting area to study as some of the

emulsions prepared had been said to face instability problemsthat include separation and sedimentation of the preparedformulation Storage at room temperature for more than6 months would cause the prepared emulsion containingacyclovir to change in its globule size significantly Drugburstleakage has also been reported despite its good entrap-ment efficiency oral bioavailability and prolonged releasecharacteristic [18] However the system was stable if it waskept in controlled temperature (4∘C) [18 19] Thus furtherinvestigation into the compositions as well as the types oflipid used would give insightful and clearer perspective of theoral drug delivery system proposed

3 Systemic Blood Delivery(Intravenous (IV) Injections)

Numerous attempts have been made by scientists and re-searchers to develop acyclovir nanocarrier for IV injectionIn general bolus IV injection is only given to patients if veryhigh doses of acyclovir are required that is 100mgkg andorwhen serious cases of HSV infection are encountered such asherpes simplex encephalitis [20]

However delivery of acyclovir via IV injection wouldcause thrombophlebitis at the injection area Also high dosesof acyclovir could cause deposition of acyclovir crystals in thekidney especially if acyclovir is given via bolus IV injectionwhere themaximumsolubility is reachedThis eventmay leadto intratubular renal damage and hence renal failure [21ndash23]This is one of the common side effects if acyclovir dose is notadjusted or proper hydration is not given [24]

Novel IV stealthy nanoparticles using polylactic cogly-colic acid (PLGA) have been developed to address theinherent issue of poor acyclovir bioavailability The objectiveof this new system is to increase its mean residence time andplasma half-life The PLGA nanovehicles have been provento extend circulation time (longer mean residence time) foracyclovir that is up to 48 hours when compared to its control(plain drug solution) Studies have also shown that spherical-shaped PLGA nanoparticles have relatively good percentageof drug entrapment where more than 60 of drug addedwas entrapped in this carrier system Acyclovir in PLGAnanocarrier yielded a reasonable particle size ranging from200 nm to 300 nm [25 26]

A study in the use of acyclovir PLGA nanoparticles inrats has revealed a much improved acyclovir biodistributionin which the concentration of acyclovir PLGA nanoparticleswas highest in hepatocytes compared to other organs (iekidney and lungs) after an intravenous injection of the drugwas given through the tail vein [26] This is an exampleof a successful targeted drug delivery with prolonged andcontinuous drug release at the site-specific organ most likelycontributed by the types of drug carriers that interactedwithbound to the surrounding cell in this case hepatocytesAs acyclovir is also a useful therapeutic agent in treatingpatients with life-threatening infectious liver disease (eghepatitis B) the study provides promising evidence of util-ising this delivery system to carry acyclovir into the body

Self-assembled nanoparticles (SAN) formulated fromacyclovir lipid derivative (SGSA) have been claimed to be

4 Journal of Nanomaterials

stable during storage at room temperature SAN maintainedits particle size of 832 nm up to one year of storage andno particles aggregation was observed Further stability testson prepared SAN which included high speed centrifugation(up to 8000 rpm) with addition of selected additives haveshown that SGSA did not show any significant differencewhen compared with the control group However SGSA wasreported to have a short elimination time (7 hours) withcells toxicity observed This is an indication of a shorter resi-dencecirculation time of acyclovir in blood and cytotoxicityof the nanoparticles should be subjected to close scrutiny infuture research [27]

Factors such as composition and compatibility of eachcomponent used in the formulation and methods utilised inthe production process may impact the physical profiles ofthe resultant product prepared These factors may affect thesize stability and pharmacokinetic and pharmacodynamiccharacteristics of the nanoparticles formed Enhanced tech-nique and improved formulations to deliver acyclovir via IVinjection continue to attract interest from researchers andfurther investigations would be worthy of note

4 Topical and Transdermal Applications

Skin lesion and blisters due to infection of HSV can betreated with the application of acyclovir in the form of topicalointment or transdermal cream Topical and transdermalformulations act as vehicles for antiviral agents besidesrendering protective layer to prevent further virus entry andspread from a particular site of infectionThese formulationsalso improve the healing time of cold sores and blisters asthe application is localised at the site of infection Howeveracyclovir ointment has been reported to have only moderateefficacy depending on the severity of the infection and theclinical condition of patientsMoreover frequent applicationsof acyclovir topical creamare required to attain its therapeuticeffect [31 32] Also it has been reported that acyclovir creamand ointment have difficulties in penetrating the epidermallayer of the skin [31] Due to slow absorption of the drugat the site of application research into new and improvedformulations for acyclovir topical ointment has receivedsignificant attention

Additionally nanoemulsion and to an extent microemul-sion-based topical formulations have been developed fortreatment of cutaneous herpes infection The applications ofthese acyclovir formulations exhibited good skin permeationprofile and resulted in HSV-1 suppression at the site ofinfection [33 34] A study on the effect of microemulsion-based topical formulations of acyclovir for the treatment ofcutaneous herpetic infections showed a positive improve-ment where no herpetic skin lesion was observed after oneweek of treatment [34] In this study 25 transcutol (ethoxy-diglycol) microemulsion containing 075mg of acyclovir wasapplied once daily to female Balbc mice at 24 hours afterinfection and compared to its control group Furthermorethe formulations were found to be stable when kept on shelfat a room temperature of 25∘C for up to 45 days [34]

Although further investigations are required to closelyscrutinize its antiviral effect a study has confirmed that

application of acyclovir emulsion for treatment of skin HSVinfection enhanced the healing time due to improvementof its skin permeation profile Schwarz and colleage havealso postulated that acyclovir nanoemulsions formulationsusing natural sugar surfactant and Solutol HS 15 couldbe a suitable candidate for topical acyclovir delivery thatshould be developed as future drug vehicles [33] Thesefindings suggested that drug carrier should not only possessgood physicochemical stability and drug loading capacitybut also be made of skin-friendly materials and be capableof penetrating the skin barrier that allows interaction withthe surrounding cells ensuring sustained drug release to thetargeted area

Beside emulsions colloidal dispersion drug deliverysystem has also been exploited for dermal delivery ofacyclovir A detailed in vitro comparative study betweenethosomes and solid lipid nanoparticles (SLNs) as acyclovirdrug carriers reported improved drug encapsulation withcomparable ability to carry high amount of acyclovir Theethosomal system utilising phosphatidylcholine showed 94drug encapsulation which was 39 higher than tristearinsolid lipid nanoparticle These systems showed similar sizeof particles of 257 nm and 236 nm respectively Evaluationstudy on antiviral activity of both acyclovir formulationsin plaque reduction assay of infected Vero cells culturesproduced similar results when compared to control (plainacyclovir solution) [35] Thus it could be concluded thatboth formulations did not affect the efficacy of the drug Inaddition data obtained from an in vitro release kinetic studysuggested that ethosomes and SLNs have sustained-releasecharacteristic where continuous drug delivery of acyclovirwas observed This positive characteristic should be furtherexploited

Typically drug prepared in a form of gel using in situgelling system is suitable for topical administration as itoffers site-specific and targeted drug delivery Encapsulatedacyclovir in polymer nanoparticles dispersion gelling sys-tem such as Pluronic F127 is not subjected to topical andtransdermal application only but also nasal and vaginaldeliveries Ramyadevi and Sandhya reported that regardlessof its wide range of particles size distribution (between 68 nmand 1281 nm) the system exhibited reasonable drug loadingcapacity (between 30 and 60) with up to 8 hours ofsustained-release profile In fact both characteristics hadfulfilled the main objective of the study a modified dosageform of acyclovir for delivery to the skin [36] Furtherinvestigations on its in vivo bioavailability would be worthy ofadditional information for the system developed Thereforeintense research and work progress in this area are requiredthat is the toxicity and the stability of the formulationin order to improve the current findings for better andpromising drug delivery methods and preparations

5 Ocular Delivery

Besides topical ointment acyclovir has also been targeted forits ocular delivery Ocular HSV infection occurs when HSVtype 1 infects the sensory neurons of the eye To date herpetickeratitis is one of the most common infectious eye diseases

Journal of Nanomaterials 5

associated with HSV [37] Prolonged herpes keratitis due tolack of treatment or recurrent infection of HSV at the samearea of the cornea would cause dendritic ulcer Eventuallythis event may cause visual impairment or worse blindnessdue to scarring and damage formed in the infected area[38 39]

Acyclovir is not prescribed to patients in the form of eyedrops because of its poor ocular bioavailability and thera-peutic efficacy due to low solubility in water On top of thatdevelopment of drug for delivery to the eye is very challeng-ing There are few factors that need to be taken into consid-eration when designing drug for ocular delivery Eyes havetheir own physical and biological protective mechanismsthat protect them from foreign substances including drugsFor example blinking and tears will reduce andor removeophthalmic drug solution from the conjunctiva There-fore it is quite difficult to get the actual dose of drugto reach the targeted tissue area hence resulting in lowocular drug absorption [40] Treatment of ocular HSV inimmunocompetent patients is prescription of oral acyclovir(800mg daily) andor continuous application of 3 acy-clovir ophthalmic ointment to the cornea area five timesdaily [30 41]

In the last decade a pioneer studywas conducted to inves-tigate the potential of liposome as acyclovir delivery vehicleLiposome offers great advantages as a colloidal drug carrierit is made of biodegradable materials and is nontoxic to cellsBy virtue of that nanosized liposomesmade of phosphatidyl-choline-cholesterol-dimethyl dioctadecyl had been devel-oped to transport acyclovir to the eyes Characteristics ofthe liposomes prepared from different procedures and mem-brane charges were evaluated Data of the study suggestedthat only charged membranes (either positively or negativelycharged liposomes) could interact with acyclovir Negativelycharged liposomes showed the highest drug entrapment effi-ciency when compared with neutral and positively chargedliposomes which could be due to greater aqueous phaseentrapmentwithin the corewhere acyclovir was placedHow-ever only positively charged liposomes showed enhancedocular acyclovir bioavailability in the aqueous humor Thiscould be due to corneal permeability adjustment made byliposomes which allows more drug to enter the cornea area[42]

In agreement with previous study positively chargedliposome was also reported to be bound to and coated onthe corneal surface and enhanced the absorption of acyclovirin the cornea Also longer acyclovir residence time of thepositively charged liposomes was observed in the aqueoushumor of the rabbits due to corneal adhesion as comparedto the commercially available acyclovir ointment [43 44] Insummary a few factors have been discovered to influence theimprovement of acyclovir-liposomes ophthalmic deliverywhich includes rate of corneal permeation and surface chargeof the fabricated liposomes such that it binds to and coats thenegatively charged corneal surface

Besides liposomes poly(ethylene glycol)-co-cyclic acetal(PECA) and polylactic acid (PLA) nanospheres coated withpolyethylene glycol (PEG) with average diameter of 200 nmcould also be a good and suitable drug vehicle for acyclovir

Acyclovir-loaded PECA and PLA nanospheres have demon-strated sustained-release property with mean residence timeof up to 6 hours [45 46] In vivoDraize tests were conductedand findings suggested that nanospheres made from bothtypes of polymer were well tolerated with no eye inflam-mation observed Thus acyclovir-loaded nanospheres wereconsidered safe for ocular use since changes were not seen inthe rabbitrsquos eyes

Acyclovir-loaded PEG coated nanospheres had shown asignificant increase of acyclovir concentration in the aqueoushumor when compared with acyclovir solution These couldhave resulted from higher drug loading capacity and betterocular mucoadhesion of the formulated nanospheres Gooddrug loading capacity and high ocular bioavailability areindication of a successful trial of acyclovir encapsulationfor its ocular delivery Data of the studies suggested thatdrug entrapment efficiency is subjected to environmentand preparation conditions (ie pH and temperature) andtypes and molecular weight of the surfactant and polymerused in the formulation In addition the compositionconcentration and ratio of surfactant and polymer usedin the formulation might influence the physicochemicalproperties of lipid nanoparticles and the ocular tolerabil-ity [47ndash49] Further investigation to test the nanospheresrsquoshelf-life stability will be beneficial for future ocular drugdelivery development

More recently solid lipid nanoparticles have been intro-duced to be a carrier system to deliver poorly water-soluble andor hydrophobic drug It offers many advan-tages over the older colloidal drug delivery systems whichinclude biocompatibility biodegradability and beingmade ofsafenontoxic materials [50 51]Thus as a stable drug carriersolid lipid nanoparticles have been proposed to be a drugvehicle for ophthalmic delivery of acyclovir Acyclovir hasbeen successfully incorporated into solid lipid nanoparticlesmade from glyceryl dibehanate Compritol 888 ATO usingthe modified hot-oil-in-water microemulsion techniqueThemorphology stability and other characteristics of the newlysynthesized nanoparticles were determined before they weretested in excised bovine cornea It was reported that thenegatively charged nanoparticle displayed poor permeationthrough cornea although it exhibited sustained-release profileto supply acyclovir for a longer period of timeHence in orderto overcome the drawback solid lipid nanoparticles havebeen physically converted to nanostructured lipid carriers(400ndash777 nm in diameter) with good drug loading capacitycharacteristic [52]

Besides having good drug entrapment efficiency of up to90 the nanostructured lipid carrier system also enhancedthe acyclovir corneal permeation This has caused an incre-ment of acyclovir cell uptake and its corneal bioavailabilityApart from that chitosan-coated nanostructured lipid carrieralso improved the antiviral efficacy of acyclovir by 35-fold after 24-hour exposure in the cornea of albino rabbitswhen compared with the commercial acyclovir ophthalmicointment available in the market [52 53] The physicochem-ical properties and structures of the formulated solid lipidnanoparticles (ie where acyclovir is loaded in the system)directly influence the bioavailability of acyclovir and rate of

6 Journal of Nanomaterials

corneal permeation as well as its stability These are amongthe important measures for a successful development ofophthalmic drug delivery

6 Conclusion

The development of nanosized drug delivery system forantiviral drugs specifically acyclovir has shown a very goodprogress and high potential to become successful for futurebenefits The delivery of acyclovir through different routes ofadministration in different forms of formulations (ie tabletssuspension and ointment) is substantial in treating patientswith HSV where infection can be mild to one individualbut severe to others depending on their health status Yeteach route of administration has its own disadvantages andside effects Alternative acyclovir delivery system is indeed avery good research area to explore The forthcoming com-mercialization of the end product will be the most excitingpart especially to the pharmaceutical industryNonetheless afew fundamental steps have to be carefully studied before theformulation can be commercializedMoreover it is necessarythat the selection of delivery vehicle for acyclovir be testedvia in vitro and in vivo studies Its optimized therapeuticefficacy and toxicity data can be attained as well as its stabilitytest as a prerequisite for clinical trials Although furtherresearch and studies are required to be performed the currentand up-to-date data from various studies conducted utilisingdifferent methods technology and resources have gainedworldwide attention and thus have contributed importantinformation in this area of research In fact the proposedvehicles have the potential to be commercialized to suitthe current needs for antiviral delivery to overcome itspharmacokinetic drawbacks Research in the nanodeliverysystem for acyclovir will add on to the latest knowledgeand improve our understanding in drug discovery as well asdelivery systems The new technology and system proposedwill not only benefit antiviral drug delivery but also benefitother marketed drugs with similar delivery problems

Competing Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] G B Elion ldquoThe biochemistry and mechanism of action ofacyclovirrdquo Journal of Antimicrobial Chemotherapy vol 12 pp9ndash17 1983

[2] G B Elion ldquoAcyclovir discovery mechanism of action andselectivityrdquo Journal of Medical Virology vol 1 supplement 1 pp2ndash6 1993

[3] J Piret and G Boivin ldquoResistance of herpes simplex viruses tonucleoside analogues mechanisms prevalence and manage-mentrdquo Antimicrobial Agents and Chemotherapy vol 55 no 2pp 459ndash472 2011

[4] J P Smith S Weller B Johnson J Nicotera J M Luther andD W Haas ldquoPharmacokinetics of acyclovir and its metabolites

in cerebrospinal fluid and systemic circulation after adminis-tration of high-dose valacyclovir in subjects with normal andimpaired renal functionrdquo Antimicrobial Agents and Chemother-apy vol 54 no 3 pp 1146ndash1151 2010

[5] R J Whitley M R Blum N Barton and P DeMiranda ldquoPhar-macokinetics of acyclovir in humans following intravenousadministration A model for the development of parenteralantiviralsrdquoThe American Journal of Medicine vol 73 no 1 pp165ndash171 1982

[6] J-M Poirier N Radembino and P Jaillon ldquoDetermination ofacyclovir in plasma by solid-phase extraction and column liquidchromatographyrdquo Therapeutic Drug Monitoring vol 21 no 1pp 129ndash133 1999

[7] M Kubbinga M A Nguyen P Staubach S Teerenstra and PLangguth ldquoThe influence of chitosan on the oral bioavailabilityof acyclovirmdasha comparative bioavailability study in humansrdquoPharmaceutical Research vol 32 no 7 pp 2241ndash2249 2015

[8] A Wald J Benedetti G Davis M Remington C Winterand L Corey ldquoA randomized double-blind comparative trialcomparing high- and standard-dose oral acyclovir for first-episode genital herpes infectionsrdquo Antimicrobial Agents andChemotherapy vol 38 no 2 pp 174ndash176 1994

[9] Y J Bryson M Dillon M Lovett et al ldquoTreatment of firstepisodes of genital herpes simplex virus infection with oral acy-clovir A randomized double-blind controlled trial in normalsubjectsrdquoTheNew England Journal of Medicine vol 308 no 16pp 916ndash921 1983

[10] G W Raborn W T McGaw M Grace L D Tyrrell and SM Samuels ldquoOral acyclovir and herpes labialis a randomizeddouble-blind placebo-controlled studyrdquo The Journal of theAmerican Dental Association vol 115 no 1 pp 38ndash42 1987

[11] H Shirazi M Daneshpour S Kashanian and K OmidfarldquoSynthesis characterization and in vitro biocompatibility studyof AuTMCFe3O4 nanocomposites as a promising nontoxicsystem for biomedical applicationsrdquo Beilstein Journal of Nan-otechnology vol 6 no 1 pp 1677ndash1689 2015

[12] M B Chaudhari P P Desai P A Patel and V B PatravaleldquoSolid lipid nanoparticles of amphotericin B (AmbiOnp) invitro and in vivo assessment towards safe and effective oraltreatment modulerdquo Drug Delivery and Translational Researchvol 6 no 4 pp 354ndash364 2016

[13] Y Oh N Lee H W Kang and J Oh ldquoIn vitro study onapoptotic cell death by effective magnetic hyperthermia withchitosan-coated MnFe2O4rdquo Nanotechnology vol 27 no 11article 115101 2016

[14] B Sapra PThatai S Bhandari J SoodM Jindal andA TiwaryldquoA critical appraisal of microemulsions for drug deliverymdashpartIrdquoTherapeutic Delivery vol 4 no 12 pp 1547ndash1564 2013

[15] D Patel and K K Sawant ldquoOral bioavailability enhancementof acyclovir by self-microemulsifying drug delivery systems(SMEDDS)rdquo Drug Development and Industrial Pharmacy vol33 no 12 pp 1318ndash1326 2007

[16] P KGhosh R JMajithiyaM LUmrethia andR S RMurthyldquoDesign and development of microemulsion drug deliverysystem of acyclovir for improvement of oral bioavailabilityrdquoAAPS PharmSciTech vol 7 no 3 p 77 2006

[17] A Gandhi S Jana and K K Sen ldquoIn-vitro release of acyclovirloaded Eudragit RLPO nanoparticles for sustained drug deliv-eryrdquo International Journal of Biological Macromolecules vol 67pp 478ndash482 2014

[18] S Paul A Kumar P Yedurkar and K Sawant ldquoDesign anddevelopment of multiple emulsion for enhancement of oral

Journal of Nanomaterials 7

bioavailability of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 11 pp 1809ndash1817 2013

[19] B B Ghera F Perret Y Chevalier and H Parrot-LopezldquoNovel nanoparticles made from amphiphilic perfluoroalkyl120572-cyclodextrin derivatives preparation characterization andapplication to the transport of acyclovirrdquo International Journalof Pharmaceutics vol 375 no 1-2 pp 155ndash162 2009

[20] U Sili A Kaya A Mert et al ldquoHerpes simplex virus encephali-tis clinical manifestations diagnosis and outcome in 106 adultpatientsrdquo Journal of Clinical Virology vol 60 no 2 pp 112ndash1182014

[21] X Zhang Y Li H Zhou et al ldquoPlasma metabolic profilinganalysis of nephrotoxicity induced by acyclovir using metabo-nomics coupled with multivariate data analysisrdquo Journal ofPharmaceutical and Biomedical Analysis C vol 97 pp 151ndash1562014

[22] A Seedat and G Winnett ldquoAcyclovir-induced acute renalfailure and the importance of an expanding waist linerdquo BMJCase Reports 2012

[23] H Lu Y-J Han J-D Xu W-M Xing and J Chen ldquoPro-teomic characterization of acyclovir-induced nephrotoxicity ina mouse modelrdquo PLoS ONE vol 9 no 7 Article ID e1031852014

[24] R Fleischer and M Johnson ldquoAcyclovir nephrotoxicity a casereport highlighting the importance of prevention detectionand treatment of acyclovir-induced nephropathyrdquo Case Reportsin Medicine vol 2010 Article ID 602783 3 pages 2010

[25] A O Kamel G A S Awad A S Geneidi and N D MortadaldquoPreparation of intravenous stealthy acyclovir nanoparticleswith increased mean residence timerdquo AAPS PharmSciTech vol10 no 4 pp 1427ndash1436 2009

[26] S Gupta A Agarwal N K Gupta G Saraogi H Agrawal andG P Agrawal ldquoGalactose decorated PLGA nanoparticles forhepatic delivery of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 12 pp 1866ndash1873 2013

[27] Y Jin L Tong P Ai M Li and X Hou ldquoSelf-assembled drugdelivery systems 1 Properties and in vitroin vivo behaviorof acyclovir self-assembled nanoparticles (SAN)rdquo InternationalJournal of Pharmaceutics vol 309 no 1-2 pp 199ndash207 2006

[28] S Rao M J Abzug P Carosone-Link et al ldquoIntravenousacyclovir and renal dysfunction in children A Matched CaseControl Studyrdquo The Journal of Pediatrics vol 166 no 6 pp1462e4ndash1468e4 2015

[29] A B Nair ldquoQuantification of uptake and clearance of acyclovirin skin layersrdquo Antiviral Therapy vol 21 no 1 pp 17ndash25 2015

[30] S Ghosh V Jhanji E Lamoureux H R Taylor and R BVajpayee ldquoAcyclovir therapy in prevention of recurrent herpetickeratitis following penetrating keratoplastyrdquo American Journalof Ophthalmology vol 145 no 2 pp 198ndash202 2008

[31] G E Parry P Dunn V P Shah and L K Pershing ldquoAcyclovirbioavailability in human skinrdquo The Journal of InvestigativeDermatology vol 98 no 6 pp 856ndash863 1992

[32] S A Qureshi M Jiang K K Midha and J P Skelly ldquoInvitro evaluation of percutaneous absorption of an acyclovirproduct using intact and tape-stripped human skinrdquo Journal ofPharmacy amp Pharmaceutical Sciences vol 1 no 3 pp 102ndash1071998

[33] J C Schwarz V Klang S Karall D Mahrhauser G P Reschand C Valenta ldquoOptimisation of multiple WOW nanoemul-sions for dermal delivery of aciclovirrdquo International Journal ofPharmaceutics vol 435 no 1 pp 69ndash75 2012

[34] G Shishu S Rajan and Kamalpreet ldquoDevelopment of novelmicroemulsion-based topical formulations of acyclovir for thetreatment of cutaneous herpetic infectionsrdquo AAPS Pharm-SciTech vol 10 no 2 pp 559ndash565 2009

[35] R Cortesi L Ravani E Menegatti M Drechsler and EEsposito ldquoColloidal dispersions for the delivery of acyclovir AComparative Studyrdquo Indian Journal of Pharmaceutical Sciencesvol 73 no 6 pp 687ndash693 2011

[36] D Ramyadevi and P Sandhya ldquoDual sustained release deliverysystem for multiple route therapy of an antiviral drugrdquo DrugDelivery vol 21 no 4 pp 276ndash292 2014

[37] E Miserocchi G Fogliato I Bianchi F Bandello and GModorati ldquoClinical features of ocular herpetic infection in anItalian referral centerrdquo Cornea vol 33 no 6 pp 565ndash570 2014

[38] S Burrel D Boutolleau G Azar et al ldquoPhenotypic andgenotypic characterization of acyclovir-resistant corneal HSV-1 isolates from immunocompetent patients with recurrentherpetic keratitisrdquo Journal of Clinical Virology vol 58 no 1 pp321ndash324 2013

[39] O Alekseev A H Tran and J Azizkhan-Clifford ldquoEx vivoorganotypic corneal model of acute epithelial herpes simplexvirus type I infectionrdquo Journal of Visualized Experiments no 69Article ID e3631 2012

[40] C Bucolo F Drago and S Salomone ldquoOcular drug deliverya clue from nanotechnologyrdquo Frontiers in Pharmacology vol 3article 188 2012

[41] D D Garcia Q Farjo D C Musch and A Sugar ldquoEffect ofprophylactic oral acyclovir after penetrating keratoplasty forherpes simplex keratitisrdquo Cornea vol 26 no 8 pp 930ndash9342007

[42] M Fresta A M Panico C Bucolo C Giannavola and GPuglisi ldquoCharacterization and in-vivo ocular absorption ofliposome-encapsulated acyclovirrdquoThe Journal of Pharmacy andPharmacology vol 51 no 5 pp 565ndash576 1999

[43] S L Law K J Huang and C H Chiang ldquoAcyclovir-containingliposomes for potential ocular delivery corneal penetration andabsorptionrdquo Journal of Controlled Release vol 63 no 1-2 pp135ndash140 2000

[44] P Chetoni S Rossi S Burgalassi D Monti S Mariotti and MF Saettone ldquoComparison of liposome-encapsulated acyclovirwith acyclovir ointment ocular pharmacokinetics in rabbitsrdquoJournal of Ocular Pharmacology andTherapeutics vol 20 no 2pp 169ndash177 2004

[45] C Giannavola C Bucolo A Maltese et al ldquoInfluence ofpreparation conditions on acyclovir-loaded poly-dl-lactic acidnanospheres and effect of PEG coating on ocular drug bioavail-abilityrdquo Pharmaceutical Research vol 20 no 4 pp 584ndash5902003

[46] M Fresta G Fontana C Bucolo G Cavallaro G Giammonaand G Puglisi ldquoOcular tolerability and in vivo bioavailability ofpoly(ethylene glycol) (PEG)-coated polyethyl-2-cyanoacrylatenanosphere-encapsulated acyclovirrdquo Journal of PharmaceuticalSciences vol 90 no 3 pp 288ndash297 2001

[47] A Leonardi C Bucolo G L Romano et al ldquoInfluence ofdifferent surfactants on the technological properties and in vivoocular tolerability of lipid nanoparticlesrdquo International Journalof Pharmaceutics vol 470 no 1-2 pp 133ndash140 2014

[48] R Pignatello C Bucolo and G Puglisi ldquoOcular tolerability ofEudragit RS100 and RL100 nanosuspensions as carriers forophthalmic controlled drug deliveryrdquo Journal of PharmaceuticalSciences vol 91 no 12 pp 2636ndash2641 2002

8 Journal of Nanomaterials

[49] C Bucolo A Maltese F Maugeri B Busa G Puglisi and RPignatello ldquoEudragit RL100 nanoparticle system for the oph-thalmic delivery of cloricromenerdquoThe Journal of Pharmacy andPharmacology vol 56 no 7 pp 841ndash846 2004

[50] S Misra K Chopra V R Sinha and B Medhi ldquoGalantamine-loaded solidndashlipid nanoparticles for enhanced brain deliverypreparation characterization in vitro and in vivo evaluationsrdquoDrug Delivery vol 23 no 4 pp 1434ndash1443 2016

[51] J Albuquerque C C Moura B Sarmento and S ReisldquoSolid lipid nanoparticles a potential multifunctional approachtowards rheumatoid arthritis theranosticsrdquo Molecules vol 20no 6 pp 11103ndash11118 2015

[52] A Seyfoddin and R Al-Kassas ldquoDevelopment of solid lipidnanoparticles and nanostructured lipid carriers for improvingocular delivery of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 4 pp 508ndash519 2013

[53] A Seyfoddin T Sherwin D V Patel et al ldquoEx vivo and in vivoevaluation of chitosan coated nanostructured lipid carriers forocular delivery of acyclovirrdquo Current Drug Delivery In press

Submit your manuscripts athttpwwwhindawicom

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CorrosionInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Polymer ScienceInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CeramicsJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CompositesJournal of

NanoparticlesJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Biomaterials

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

NanoscienceJournal of

TextilesHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Journal of

NanotechnologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

CrystallographyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CoatingsJournal of

Advances in

Materials Science and EngineeringHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Smart Materials Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MetallurgyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

MaterialsJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Nano

materials

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal ofNanomaterials

Journal of Nanomaterials 3

administration Some of the common side effects of orallydelivered acyclovir are nausea vomiting diarrhoea andheadache [8] In order to obtain therapeutic effect of as wellas enhancing compliance and minimising its dose relatedside effects various techniques and methods for delivery ofacyclovir have been developed

A lipid nanoemulsion system has been designed andintroduced to entrap acyclovirThis emulsion system is madeup of liquid lipids which are dispersed in water and stabilizedby emulsifier andor surfactant that coat the nanosizedlipid droplets Emulsifiers or surfactants are used to reducethe interfacial tension of lipid droplets with the aqueousphase (water) Surfactant and emuslifiers are added in theformulation to avoid droplets collision in order to maintainthe desired droplet size [14] Although the emulsifying tech-nique is quite an antiquated drug preparation technique themodern technology has adapted this method to a level whereit stands together with other newer drug delivery formsMoreover an improvement in drug solubility will definitelyhave a positive impact on the drug bioavailability

Nanoemulsion systems for oral acyclovir delivery havebeen shown to improve acyclovir oral bioavailability in ratswhen compared with the commercially available plain drugeither in tablet form or in solutions More importantly theparticles produced were within the nanometric size rangingfrom20 nm to 40 nmwith gooddrug entrapment and loadingcapacity [15 16] In addition liquid nanoemulsion developedshowed longer blood circulation time when compared withplain drug solution In contrast it was reported that the self-microemulsifying drug delivery system which was made upof 30 glycerol 9 sunflower oil and 60 tween 60 did notexhibit a sustained-release profile Also the half-life (11990512) wasreported to be about 25 to 3 hours which was similar to thepure drug solution [15] These studies showed that types andratio of the oil to surfactant (optimized using pseudoternaryphase diagram) used in formulating the nanoemulsion playeda major role in determining the sustained-release character-istic of the nanoemulsions constructed

More recently an in vitro drug release study of acyclovir-loaded Eudragi RLPO nanoparticles showed sustained drugrelease property for over a period of 24 hours Howeverthe use of Eudragi RLPO and a stabilizer Pluronic F68might not be a good combination for formulation of oraldrug delivery vehicle due to the fact that range of particlesize produced was large between 82 and 532 nm The drugentrapment efficiency was reported to be moderate at about53ndash79 [17] Thus the composition and the ratio of bothsurfactant and polymer used in the formulation directlyinfluenced the drug entrapment efficiency and its particlesizes as well as the polydispersity index In addition largesizes and high polydispersity index particles are indicators ofinstability of a formulation and are benchmarked to estimatethe nanoparticlersquos shelf-life storage condition

A stability test is one of the most crucial steps indeveloping drug carrier Usually the stability test of a newlyformulated drug is an indicator of the product performancesover time and an important criterion for future drug com-mercialization The shelf-life stability of the nanoemulsionformulation is an interesting area to study as some of the

emulsions prepared had been said to face instability problemsthat include separation and sedimentation of the preparedformulation Storage at room temperature for more than6 months would cause the prepared emulsion containingacyclovir to change in its globule size significantly Drugburstleakage has also been reported despite its good entrap-ment efficiency oral bioavailability and prolonged releasecharacteristic [18] However the system was stable if it waskept in controlled temperature (4∘C) [18 19] Thus furtherinvestigation into the compositions as well as the types oflipid used would give insightful and clearer perspective of theoral drug delivery system proposed

3 Systemic Blood Delivery(Intravenous (IV) Injections)

Numerous attempts have been made by scientists and re-searchers to develop acyclovir nanocarrier for IV injectionIn general bolus IV injection is only given to patients if veryhigh doses of acyclovir are required that is 100mgkg andorwhen serious cases of HSV infection are encountered such asherpes simplex encephalitis [20]

However delivery of acyclovir via IV injection wouldcause thrombophlebitis at the injection area Also high dosesof acyclovir could cause deposition of acyclovir crystals in thekidney especially if acyclovir is given via bolus IV injectionwhere themaximumsolubility is reachedThis eventmay leadto intratubular renal damage and hence renal failure [21ndash23]This is one of the common side effects if acyclovir dose is notadjusted or proper hydration is not given [24]

Novel IV stealthy nanoparticles using polylactic cogly-colic acid (PLGA) have been developed to address theinherent issue of poor acyclovir bioavailability The objectiveof this new system is to increase its mean residence time andplasma half-life The PLGA nanovehicles have been provento extend circulation time (longer mean residence time) foracyclovir that is up to 48 hours when compared to its control(plain drug solution) Studies have also shown that spherical-shaped PLGA nanoparticles have relatively good percentageof drug entrapment where more than 60 of drug addedwas entrapped in this carrier system Acyclovir in PLGAnanocarrier yielded a reasonable particle size ranging from200 nm to 300 nm [25 26]

A study in the use of acyclovir PLGA nanoparticles inrats has revealed a much improved acyclovir biodistributionin which the concentration of acyclovir PLGA nanoparticleswas highest in hepatocytes compared to other organs (iekidney and lungs) after an intravenous injection of the drugwas given through the tail vein [26] This is an exampleof a successful targeted drug delivery with prolonged andcontinuous drug release at the site-specific organ most likelycontributed by the types of drug carriers that interactedwithbound to the surrounding cell in this case hepatocytesAs acyclovir is also a useful therapeutic agent in treatingpatients with life-threatening infectious liver disease (eghepatitis B) the study provides promising evidence of util-ising this delivery system to carry acyclovir into the body

Self-assembled nanoparticles (SAN) formulated fromacyclovir lipid derivative (SGSA) have been claimed to be

4 Journal of Nanomaterials

stable during storage at room temperature SAN maintainedits particle size of 832 nm up to one year of storage andno particles aggregation was observed Further stability testson prepared SAN which included high speed centrifugation(up to 8000 rpm) with addition of selected additives haveshown that SGSA did not show any significant differencewhen compared with the control group However SGSA wasreported to have a short elimination time (7 hours) withcells toxicity observed This is an indication of a shorter resi-dencecirculation time of acyclovir in blood and cytotoxicityof the nanoparticles should be subjected to close scrutiny infuture research [27]

Factors such as composition and compatibility of eachcomponent used in the formulation and methods utilised inthe production process may impact the physical profiles ofthe resultant product prepared These factors may affect thesize stability and pharmacokinetic and pharmacodynamiccharacteristics of the nanoparticles formed Enhanced tech-nique and improved formulations to deliver acyclovir via IVinjection continue to attract interest from researchers andfurther investigations would be worthy of note

4 Topical and Transdermal Applications

Skin lesion and blisters due to infection of HSV can betreated with the application of acyclovir in the form of topicalointment or transdermal cream Topical and transdermalformulations act as vehicles for antiviral agents besidesrendering protective layer to prevent further virus entry andspread from a particular site of infectionThese formulationsalso improve the healing time of cold sores and blisters asthe application is localised at the site of infection Howeveracyclovir ointment has been reported to have only moderateefficacy depending on the severity of the infection and theclinical condition of patientsMoreover frequent applicationsof acyclovir topical creamare required to attain its therapeuticeffect [31 32] Also it has been reported that acyclovir creamand ointment have difficulties in penetrating the epidermallayer of the skin [31] Due to slow absorption of the drugat the site of application research into new and improvedformulations for acyclovir topical ointment has receivedsignificant attention

Additionally nanoemulsion and to an extent microemul-sion-based topical formulations have been developed fortreatment of cutaneous herpes infection The applications ofthese acyclovir formulations exhibited good skin permeationprofile and resulted in HSV-1 suppression at the site ofinfection [33 34] A study on the effect of microemulsion-based topical formulations of acyclovir for the treatment ofcutaneous herpetic infections showed a positive improve-ment where no herpetic skin lesion was observed after oneweek of treatment [34] In this study 25 transcutol (ethoxy-diglycol) microemulsion containing 075mg of acyclovir wasapplied once daily to female Balbc mice at 24 hours afterinfection and compared to its control group Furthermorethe formulations were found to be stable when kept on shelfat a room temperature of 25∘C for up to 45 days [34]

Although further investigations are required to closelyscrutinize its antiviral effect a study has confirmed that

application of acyclovir emulsion for treatment of skin HSVinfection enhanced the healing time due to improvementof its skin permeation profile Schwarz and colleage havealso postulated that acyclovir nanoemulsions formulationsusing natural sugar surfactant and Solutol HS 15 couldbe a suitable candidate for topical acyclovir delivery thatshould be developed as future drug vehicles [33] Thesefindings suggested that drug carrier should not only possessgood physicochemical stability and drug loading capacitybut also be made of skin-friendly materials and be capableof penetrating the skin barrier that allows interaction withthe surrounding cells ensuring sustained drug release to thetargeted area

Beside emulsions colloidal dispersion drug deliverysystem has also been exploited for dermal delivery ofacyclovir A detailed in vitro comparative study betweenethosomes and solid lipid nanoparticles (SLNs) as acyclovirdrug carriers reported improved drug encapsulation withcomparable ability to carry high amount of acyclovir Theethosomal system utilising phosphatidylcholine showed 94drug encapsulation which was 39 higher than tristearinsolid lipid nanoparticle These systems showed similar sizeof particles of 257 nm and 236 nm respectively Evaluationstudy on antiviral activity of both acyclovir formulationsin plaque reduction assay of infected Vero cells culturesproduced similar results when compared to control (plainacyclovir solution) [35] Thus it could be concluded thatboth formulations did not affect the efficacy of the drug Inaddition data obtained from an in vitro release kinetic studysuggested that ethosomes and SLNs have sustained-releasecharacteristic where continuous drug delivery of acyclovirwas observed This positive characteristic should be furtherexploited

Typically drug prepared in a form of gel using in situgelling system is suitable for topical administration as itoffers site-specific and targeted drug delivery Encapsulatedacyclovir in polymer nanoparticles dispersion gelling sys-tem such as Pluronic F127 is not subjected to topical andtransdermal application only but also nasal and vaginaldeliveries Ramyadevi and Sandhya reported that regardlessof its wide range of particles size distribution (between 68 nmand 1281 nm) the system exhibited reasonable drug loadingcapacity (between 30 and 60) with up to 8 hours ofsustained-release profile In fact both characteristics hadfulfilled the main objective of the study a modified dosageform of acyclovir for delivery to the skin [36] Furtherinvestigations on its in vivo bioavailability would be worthy ofadditional information for the system developed Thereforeintense research and work progress in this area are requiredthat is the toxicity and the stability of the formulationin order to improve the current findings for better andpromising drug delivery methods and preparations

5 Ocular Delivery

Besides topical ointment acyclovir has also been targeted forits ocular delivery Ocular HSV infection occurs when HSVtype 1 infects the sensory neurons of the eye To date herpetickeratitis is one of the most common infectious eye diseases

Journal of Nanomaterials 5

associated with HSV [37] Prolonged herpes keratitis due tolack of treatment or recurrent infection of HSV at the samearea of the cornea would cause dendritic ulcer Eventuallythis event may cause visual impairment or worse blindnessdue to scarring and damage formed in the infected area[38 39]

Acyclovir is not prescribed to patients in the form of eyedrops because of its poor ocular bioavailability and thera-peutic efficacy due to low solubility in water On top of thatdevelopment of drug for delivery to the eye is very challeng-ing There are few factors that need to be taken into consid-eration when designing drug for ocular delivery Eyes havetheir own physical and biological protective mechanismsthat protect them from foreign substances including drugsFor example blinking and tears will reduce andor removeophthalmic drug solution from the conjunctiva There-fore it is quite difficult to get the actual dose of drugto reach the targeted tissue area hence resulting in lowocular drug absorption [40] Treatment of ocular HSV inimmunocompetent patients is prescription of oral acyclovir(800mg daily) andor continuous application of 3 acy-clovir ophthalmic ointment to the cornea area five timesdaily [30 41]

In the last decade a pioneer studywas conducted to inves-tigate the potential of liposome as acyclovir delivery vehicleLiposome offers great advantages as a colloidal drug carrierit is made of biodegradable materials and is nontoxic to cellsBy virtue of that nanosized liposomesmade of phosphatidyl-choline-cholesterol-dimethyl dioctadecyl had been devel-oped to transport acyclovir to the eyes Characteristics ofthe liposomes prepared from different procedures and mem-brane charges were evaluated Data of the study suggestedthat only charged membranes (either positively or negativelycharged liposomes) could interact with acyclovir Negativelycharged liposomes showed the highest drug entrapment effi-ciency when compared with neutral and positively chargedliposomes which could be due to greater aqueous phaseentrapmentwithin the corewhere acyclovir was placedHow-ever only positively charged liposomes showed enhancedocular acyclovir bioavailability in the aqueous humor Thiscould be due to corneal permeability adjustment made byliposomes which allows more drug to enter the cornea area[42]

In agreement with previous study positively chargedliposome was also reported to be bound to and coated onthe corneal surface and enhanced the absorption of acyclovirin the cornea Also longer acyclovir residence time of thepositively charged liposomes was observed in the aqueoushumor of the rabbits due to corneal adhesion as comparedto the commercially available acyclovir ointment [43 44] Insummary a few factors have been discovered to influence theimprovement of acyclovir-liposomes ophthalmic deliverywhich includes rate of corneal permeation and surface chargeof the fabricated liposomes such that it binds to and coats thenegatively charged corneal surface

Besides liposomes poly(ethylene glycol)-co-cyclic acetal(PECA) and polylactic acid (PLA) nanospheres coated withpolyethylene glycol (PEG) with average diameter of 200 nmcould also be a good and suitable drug vehicle for acyclovir

Acyclovir-loaded PECA and PLA nanospheres have demon-strated sustained-release property with mean residence timeof up to 6 hours [45 46] In vivoDraize tests were conductedand findings suggested that nanospheres made from bothtypes of polymer were well tolerated with no eye inflam-mation observed Thus acyclovir-loaded nanospheres wereconsidered safe for ocular use since changes were not seen inthe rabbitrsquos eyes

Acyclovir-loaded PEG coated nanospheres had shown asignificant increase of acyclovir concentration in the aqueoushumor when compared with acyclovir solution These couldhave resulted from higher drug loading capacity and betterocular mucoadhesion of the formulated nanospheres Gooddrug loading capacity and high ocular bioavailability areindication of a successful trial of acyclovir encapsulationfor its ocular delivery Data of the studies suggested thatdrug entrapment efficiency is subjected to environmentand preparation conditions (ie pH and temperature) andtypes and molecular weight of the surfactant and polymerused in the formulation In addition the compositionconcentration and ratio of surfactant and polymer usedin the formulation might influence the physicochemicalproperties of lipid nanoparticles and the ocular tolerabil-ity [47ndash49] Further investigation to test the nanospheresrsquoshelf-life stability will be beneficial for future ocular drugdelivery development

More recently solid lipid nanoparticles have been intro-duced to be a carrier system to deliver poorly water-soluble andor hydrophobic drug It offers many advan-tages over the older colloidal drug delivery systems whichinclude biocompatibility biodegradability and beingmade ofsafenontoxic materials [50 51]Thus as a stable drug carriersolid lipid nanoparticles have been proposed to be a drugvehicle for ophthalmic delivery of acyclovir Acyclovir hasbeen successfully incorporated into solid lipid nanoparticlesmade from glyceryl dibehanate Compritol 888 ATO usingthe modified hot-oil-in-water microemulsion techniqueThemorphology stability and other characteristics of the newlysynthesized nanoparticles were determined before they weretested in excised bovine cornea It was reported that thenegatively charged nanoparticle displayed poor permeationthrough cornea although it exhibited sustained-release profileto supply acyclovir for a longer period of timeHence in orderto overcome the drawback solid lipid nanoparticles havebeen physically converted to nanostructured lipid carriers(400ndash777 nm in diameter) with good drug loading capacitycharacteristic [52]

Besides having good drug entrapment efficiency of up to90 the nanostructured lipid carrier system also enhancedthe acyclovir corneal permeation This has caused an incre-ment of acyclovir cell uptake and its corneal bioavailabilityApart from that chitosan-coated nanostructured lipid carrieralso improved the antiviral efficacy of acyclovir by 35-fold after 24-hour exposure in the cornea of albino rabbitswhen compared with the commercial acyclovir ophthalmicointment available in the market [52 53] The physicochem-ical properties and structures of the formulated solid lipidnanoparticles (ie where acyclovir is loaded in the system)directly influence the bioavailability of acyclovir and rate of

6 Journal of Nanomaterials

corneal permeation as well as its stability These are amongthe important measures for a successful development ofophthalmic drug delivery

6 Conclusion

The development of nanosized drug delivery system forantiviral drugs specifically acyclovir has shown a very goodprogress and high potential to become successful for futurebenefits The delivery of acyclovir through different routes ofadministration in different forms of formulations (ie tabletssuspension and ointment) is substantial in treating patientswith HSV where infection can be mild to one individualbut severe to others depending on their health status Yeteach route of administration has its own disadvantages andside effects Alternative acyclovir delivery system is indeed avery good research area to explore The forthcoming com-mercialization of the end product will be the most excitingpart especially to the pharmaceutical industryNonetheless afew fundamental steps have to be carefully studied before theformulation can be commercializedMoreover it is necessarythat the selection of delivery vehicle for acyclovir be testedvia in vitro and in vivo studies Its optimized therapeuticefficacy and toxicity data can be attained as well as its stabilitytest as a prerequisite for clinical trials Although furtherresearch and studies are required to be performed the currentand up-to-date data from various studies conducted utilisingdifferent methods technology and resources have gainedworldwide attention and thus have contributed importantinformation in this area of research In fact the proposedvehicles have the potential to be commercialized to suitthe current needs for antiviral delivery to overcome itspharmacokinetic drawbacks Research in the nanodeliverysystem for acyclovir will add on to the latest knowledgeand improve our understanding in drug discovery as well asdelivery systems The new technology and system proposedwill not only benefit antiviral drug delivery but also benefitother marketed drugs with similar delivery problems

Competing Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] G B Elion ldquoThe biochemistry and mechanism of action ofacyclovirrdquo Journal of Antimicrobial Chemotherapy vol 12 pp9ndash17 1983

[2] G B Elion ldquoAcyclovir discovery mechanism of action andselectivityrdquo Journal of Medical Virology vol 1 supplement 1 pp2ndash6 1993

[3] J Piret and G Boivin ldquoResistance of herpes simplex viruses tonucleoside analogues mechanisms prevalence and manage-mentrdquo Antimicrobial Agents and Chemotherapy vol 55 no 2pp 459ndash472 2011

[4] J P Smith S Weller B Johnson J Nicotera J M Luther andD W Haas ldquoPharmacokinetics of acyclovir and its metabolites

in cerebrospinal fluid and systemic circulation after adminis-tration of high-dose valacyclovir in subjects with normal andimpaired renal functionrdquo Antimicrobial Agents and Chemother-apy vol 54 no 3 pp 1146ndash1151 2010

[5] R J Whitley M R Blum N Barton and P DeMiranda ldquoPhar-macokinetics of acyclovir in humans following intravenousadministration A model for the development of parenteralantiviralsrdquoThe American Journal of Medicine vol 73 no 1 pp165ndash171 1982

[6] J-M Poirier N Radembino and P Jaillon ldquoDetermination ofacyclovir in plasma by solid-phase extraction and column liquidchromatographyrdquo Therapeutic Drug Monitoring vol 21 no 1pp 129ndash133 1999

[7] M Kubbinga M A Nguyen P Staubach S Teerenstra and PLangguth ldquoThe influence of chitosan on the oral bioavailabilityof acyclovirmdasha comparative bioavailability study in humansrdquoPharmaceutical Research vol 32 no 7 pp 2241ndash2249 2015

[8] A Wald J Benedetti G Davis M Remington C Winterand L Corey ldquoA randomized double-blind comparative trialcomparing high- and standard-dose oral acyclovir for first-episode genital herpes infectionsrdquo Antimicrobial Agents andChemotherapy vol 38 no 2 pp 174ndash176 1994

[9] Y J Bryson M Dillon M Lovett et al ldquoTreatment of firstepisodes of genital herpes simplex virus infection with oral acy-clovir A randomized double-blind controlled trial in normalsubjectsrdquoTheNew England Journal of Medicine vol 308 no 16pp 916ndash921 1983

[10] G W Raborn W T McGaw M Grace L D Tyrrell and SM Samuels ldquoOral acyclovir and herpes labialis a randomizeddouble-blind placebo-controlled studyrdquo The Journal of theAmerican Dental Association vol 115 no 1 pp 38ndash42 1987

[11] H Shirazi M Daneshpour S Kashanian and K OmidfarldquoSynthesis characterization and in vitro biocompatibility studyof AuTMCFe3O4 nanocomposites as a promising nontoxicsystem for biomedical applicationsrdquo Beilstein Journal of Nan-otechnology vol 6 no 1 pp 1677ndash1689 2015

[12] M B Chaudhari P P Desai P A Patel and V B PatravaleldquoSolid lipid nanoparticles of amphotericin B (AmbiOnp) invitro and in vivo assessment towards safe and effective oraltreatment modulerdquo Drug Delivery and Translational Researchvol 6 no 4 pp 354ndash364 2016

[13] Y Oh N Lee H W Kang and J Oh ldquoIn vitro study onapoptotic cell death by effective magnetic hyperthermia withchitosan-coated MnFe2O4rdquo Nanotechnology vol 27 no 11article 115101 2016

[14] B Sapra PThatai S Bhandari J SoodM Jindal andA TiwaryldquoA critical appraisal of microemulsions for drug deliverymdashpartIrdquoTherapeutic Delivery vol 4 no 12 pp 1547ndash1564 2013

[15] D Patel and K K Sawant ldquoOral bioavailability enhancementof acyclovir by self-microemulsifying drug delivery systems(SMEDDS)rdquo Drug Development and Industrial Pharmacy vol33 no 12 pp 1318ndash1326 2007

[16] P KGhosh R JMajithiyaM LUmrethia andR S RMurthyldquoDesign and development of microemulsion drug deliverysystem of acyclovir for improvement of oral bioavailabilityrdquoAAPS PharmSciTech vol 7 no 3 p 77 2006

[17] A Gandhi S Jana and K K Sen ldquoIn-vitro release of acyclovirloaded Eudragit RLPO nanoparticles for sustained drug deliv-eryrdquo International Journal of Biological Macromolecules vol 67pp 478ndash482 2014

[18] S Paul A Kumar P Yedurkar and K Sawant ldquoDesign anddevelopment of multiple emulsion for enhancement of oral

Journal of Nanomaterials 7

bioavailability of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 11 pp 1809ndash1817 2013

[19] B B Ghera F Perret Y Chevalier and H Parrot-LopezldquoNovel nanoparticles made from amphiphilic perfluoroalkyl120572-cyclodextrin derivatives preparation characterization andapplication to the transport of acyclovirrdquo International Journalof Pharmaceutics vol 375 no 1-2 pp 155ndash162 2009

[20] U Sili A Kaya A Mert et al ldquoHerpes simplex virus encephali-tis clinical manifestations diagnosis and outcome in 106 adultpatientsrdquo Journal of Clinical Virology vol 60 no 2 pp 112ndash1182014

[21] X Zhang Y Li H Zhou et al ldquoPlasma metabolic profilinganalysis of nephrotoxicity induced by acyclovir using metabo-nomics coupled with multivariate data analysisrdquo Journal ofPharmaceutical and Biomedical Analysis C vol 97 pp 151ndash1562014

[22] A Seedat and G Winnett ldquoAcyclovir-induced acute renalfailure and the importance of an expanding waist linerdquo BMJCase Reports 2012

[23] H Lu Y-J Han J-D Xu W-M Xing and J Chen ldquoPro-teomic characterization of acyclovir-induced nephrotoxicity ina mouse modelrdquo PLoS ONE vol 9 no 7 Article ID e1031852014

[24] R Fleischer and M Johnson ldquoAcyclovir nephrotoxicity a casereport highlighting the importance of prevention detectionand treatment of acyclovir-induced nephropathyrdquo Case Reportsin Medicine vol 2010 Article ID 602783 3 pages 2010

[25] A O Kamel G A S Awad A S Geneidi and N D MortadaldquoPreparation of intravenous stealthy acyclovir nanoparticleswith increased mean residence timerdquo AAPS PharmSciTech vol10 no 4 pp 1427ndash1436 2009

[26] S Gupta A Agarwal N K Gupta G Saraogi H Agrawal andG P Agrawal ldquoGalactose decorated PLGA nanoparticles forhepatic delivery of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 12 pp 1866ndash1873 2013

[27] Y Jin L Tong P Ai M Li and X Hou ldquoSelf-assembled drugdelivery systems 1 Properties and in vitroin vivo behaviorof acyclovir self-assembled nanoparticles (SAN)rdquo InternationalJournal of Pharmaceutics vol 309 no 1-2 pp 199ndash207 2006

[28] S Rao M J Abzug P Carosone-Link et al ldquoIntravenousacyclovir and renal dysfunction in children A Matched CaseControl Studyrdquo The Journal of Pediatrics vol 166 no 6 pp1462e4ndash1468e4 2015

[29] A B Nair ldquoQuantification of uptake and clearance of acyclovirin skin layersrdquo Antiviral Therapy vol 21 no 1 pp 17ndash25 2015

[30] S Ghosh V Jhanji E Lamoureux H R Taylor and R BVajpayee ldquoAcyclovir therapy in prevention of recurrent herpetickeratitis following penetrating keratoplastyrdquo American Journalof Ophthalmology vol 145 no 2 pp 198ndash202 2008

[31] G E Parry P Dunn V P Shah and L K Pershing ldquoAcyclovirbioavailability in human skinrdquo The Journal of InvestigativeDermatology vol 98 no 6 pp 856ndash863 1992

[32] S A Qureshi M Jiang K K Midha and J P Skelly ldquoInvitro evaluation of percutaneous absorption of an acyclovirproduct using intact and tape-stripped human skinrdquo Journal ofPharmacy amp Pharmaceutical Sciences vol 1 no 3 pp 102ndash1071998

[33] J C Schwarz V Klang S Karall D Mahrhauser G P Reschand C Valenta ldquoOptimisation of multiple WOW nanoemul-sions for dermal delivery of aciclovirrdquo International Journal ofPharmaceutics vol 435 no 1 pp 69ndash75 2012

[34] G Shishu S Rajan and Kamalpreet ldquoDevelopment of novelmicroemulsion-based topical formulations of acyclovir for thetreatment of cutaneous herpetic infectionsrdquo AAPS Pharm-SciTech vol 10 no 2 pp 559ndash565 2009

[35] R Cortesi L Ravani E Menegatti M Drechsler and EEsposito ldquoColloidal dispersions for the delivery of acyclovir AComparative Studyrdquo Indian Journal of Pharmaceutical Sciencesvol 73 no 6 pp 687ndash693 2011

[36] D Ramyadevi and P Sandhya ldquoDual sustained release deliverysystem for multiple route therapy of an antiviral drugrdquo DrugDelivery vol 21 no 4 pp 276ndash292 2014

[37] E Miserocchi G Fogliato I Bianchi F Bandello and GModorati ldquoClinical features of ocular herpetic infection in anItalian referral centerrdquo Cornea vol 33 no 6 pp 565ndash570 2014

[38] S Burrel D Boutolleau G Azar et al ldquoPhenotypic andgenotypic characterization of acyclovir-resistant corneal HSV-1 isolates from immunocompetent patients with recurrentherpetic keratitisrdquo Journal of Clinical Virology vol 58 no 1 pp321ndash324 2013

[39] O Alekseev A H Tran and J Azizkhan-Clifford ldquoEx vivoorganotypic corneal model of acute epithelial herpes simplexvirus type I infectionrdquo Journal of Visualized Experiments no 69Article ID e3631 2012

[40] C Bucolo F Drago and S Salomone ldquoOcular drug deliverya clue from nanotechnologyrdquo Frontiers in Pharmacology vol 3article 188 2012

[41] D D Garcia Q Farjo D C Musch and A Sugar ldquoEffect ofprophylactic oral acyclovir after penetrating keratoplasty forherpes simplex keratitisrdquo Cornea vol 26 no 8 pp 930ndash9342007

[42] M Fresta A M Panico C Bucolo C Giannavola and GPuglisi ldquoCharacterization and in-vivo ocular absorption ofliposome-encapsulated acyclovirrdquoThe Journal of Pharmacy andPharmacology vol 51 no 5 pp 565ndash576 1999

[43] S L Law K J Huang and C H Chiang ldquoAcyclovir-containingliposomes for potential ocular delivery corneal penetration andabsorptionrdquo Journal of Controlled Release vol 63 no 1-2 pp135ndash140 2000

[44] P Chetoni S Rossi S Burgalassi D Monti S Mariotti and MF Saettone ldquoComparison of liposome-encapsulated acyclovirwith acyclovir ointment ocular pharmacokinetics in rabbitsrdquoJournal of Ocular Pharmacology andTherapeutics vol 20 no 2pp 169ndash177 2004

[45] C Giannavola C Bucolo A Maltese et al ldquoInfluence ofpreparation conditions on acyclovir-loaded poly-dl-lactic acidnanospheres and effect of PEG coating on ocular drug bioavail-abilityrdquo Pharmaceutical Research vol 20 no 4 pp 584ndash5902003

[46] M Fresta G Fontana C Bucolo G Cavallaro G Giammonaand G Puglisi ldquoOcular tolerability and in vivo bioavailability ofpoly(ethylene glycol) (PEG)-coated polyethyl-2-cyanoacrylatenanosphere-encapsulated acyclovirrdquo Journal of PharmaceuticalSciences vol 90 no 3 pp 288ndash297 2001

[47] A Leonardi C Bucolo G L Romano et al ldquoInfluence ofdifferent surfactants on the technological properties and in vivoocular tolerability of lipid nanoparticlesrdquo International Journalof Pharmaceutics vol 470 no 1-2 pp 133ndash140 2014

[48] R Pignatello C Bucolo and G Puglisi ldquoOcular tolerability ofEudragit RS100 and RL100 nanosuspensions as carriers forophthalmic controlled drug deliveryrdquo Journal of PharmaceuticalSciences vol 91 no 12 pp 2636ndash2641 2002

8 Journal of Nanomaterials

[49] C Bucolo A Maltese F Maugeri B Busa G Puglisi and RPignatello ldquoEudragit RL100 nanoparticle system for the oph-thalmic delivery of cloricromenerdquoThe Journal of Pharmacy andPharmacology vol 56 no 7 pp 841ndash846 2004

[50] S Misra K Chopra V R Sinha and B Medhi ldquoGalantamine-loaded solidndashlipid nanoparticles for enhanced brain deliverypreparation characterization in vitro and in vivo evaluationsrdquoDrug Delivery vol 23 no 4 pp 1434ndash1443 2016

[51] J Albuquerque C C Moura B Sarmento and S ReisldquoSolid lipid nanoparticles a potential multifunctional approachtowards rheumatoid arthritis theranosticsrdquo Molecules vol 20no 6 pp 11103ndash11118 2015

[52] A Seyfoddin and R Al-Kassas ldquoDevelopment of solid lipidnanoparticles and nanostructured lipid carriers for improvingocular delivery of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 4 pp 508ndash519 2013

[53] A Seyfoddin T Sherwin D V Patel et al ldquoEx vivo and in vivoevaluation of chitosan coated nanostructured lipid carriers forocular delivery of acyclovirrdquo Current Drug Delivery In press

Submit your manuscripts athttpwwwhindawicom

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CorrosionInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Polymer ScienceInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CeramicsJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CompositesJournal of

NanoparticlesJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Biomaterials

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

NanoscienceJournal of

TextilesHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Journal of

NanotechnologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

CrystallographyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CoatingsJournal of

Advances in

Materials Science and EngineeringHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Smart Materials Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MetallurgyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

MaterialsJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Nano

materials

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal ofNanomaterials

4 Journal of Nanomaterials

stable during storage at room temperature SAN maintainedits particle size of 832 nm up to one year of storage andno particles aggregation was observed Further stability testson prepared SAN which included high speed centrifugation(up to 8000 rpm) with addition of selected additives haveshown that SGSA did not show any significant differencewhen compared with the control group However SGSA wasreported to have a short elimination time (7 hours) withcells toxicity observed This is an indication of a shorter resi-dencecirculation time of acyclovir in blood and cytotoxicityof the nanoparticles should be subjected to close scrutiny infuture research [27]

Factors such as composition and compatibility of eachcomponent used in the formulation and methods utilised inthe production process may impact the physical profiles ofthe resultant product prepared These factors may affect thesize stability and pharmacokinetic and pharmacodynamiccharacteristics of the nanoparticles formed Enhanced tech-nique and improved formulations to deliver acyclovir via IVinjection continue to attract interest from researchers andfurther investigations would be worthy of note

4 Topical and Transdermal Applications

Skin lesion and blisters due to infection of HSV can betreated with the application of acyclovir in the form of topicalointment or transdermal cream Topical and transdermalformulations act as vehicles for antiviral agents besidesrendering protective layer to prevent further virus entry andspread from a particular site of infectionThese formulationsalso improve the healing time of cold sores and blisters asthe application is localised at the site of infection Howeveracyclovir ointment has been reported to have only moderateefficacy depending on the severity of the infection and theclinical condition of patientsMoreover frequent applicationsof acyclovir topical creamare required to attain its therapeuticeffect [31 32] Also it has been reported that acyclovir creamand ointment have difficulties in penetrating the epidermallayer of the skin [31] Due to slow absorption of the drugat the site of application research into new and improvedformulations for acyclovir topical ointment has receivedsignificant attention

Additionally nanoemulsion and to an extent microemul-sion-based topical formulations have been developed fortreatment of cutaneous herpes infection The applications ofthese acyclovir formulations exhibited good skin permeationprofile and resulted in HSV-1 suppression at the site ofinfection [33 34] A study on the effect of microemulsion-based topical formulations of acyclovir for the treatment ofcutaneous herpetic infections showed a positive improve-ment where no herpetic skin lesion was observed after oneweek of treatment [34] In this study 25 transcutol (ethoxy-diglycol) microemulsion containing 075mg of acyclovir wasapplied once daily to female Balbc mice at 24 hours afterinfection and compared to its control group Furthermorethe formulations were found to be stable when kept on shelfat a room temperature of 25∘C for up to 45 days [34]

Although further investigations are required to closelyscrutinize its antiviral effect a study has confirmed that

application of acyclovir emulsion for treatment of skin HSVinfection enhanced the healing time due to improvementof its skin permeation profile Schwarz and colleage havealso postulated that acyclovir nanoemulsions formulationsusing natural sugar surfactant and Solutol HS 15 couldbe a suitable candidate for topical acyclovir delivery thatshould be developed as future drug vehicles [33] Thesefindings suggested that drug carrier should not only possessgood physicochemical stability and drug loading capacitybut also be made of skin-friendly materials and be capableof penetrating the skin barrier that allows interaction withthe surrounding cells ensuring sustained drug release to thetargeted area

Beside emulsions colloidal dispersion drug deliverysystem has also been exploited for dermal delivery ofacyclovir A detailed in vitro comparative study betweenethosomes and solid lipid nanoparticles (SLNs) as acyclovirdrug carriers reported improved drug encapsulation withcomparable ability to carry high amount of acyclovir Theethosomal system utilising phosphatidylcholine showed 94drug encapsulation which was 39 higher than tristearinsolid lipid nanoparticle These systems showed similar sizeof particles of 257 nm and 236 nm respectively Evaluationstudy on antiviral activity of both acyclovir formulationsin plaque reduction assay of infected Vero cells culturesproduced similar results when compared to control (plainacyclovir solution) [35] Thus it could be concluded thatboth formulations did not affect the efficacy of the drug Inaddition data obtained from an in vitro release kinetic studysuggested that ethosomes and SLNs have sustained-releasecharacteristic where continuous drug delivery of acyclovirwas observed This positive characteristic should be furtherexploited

Typically drug prepared in a form of gel using in situgelling system is suitable for topical administration as itoffers site-specific and targeted drug delivery Encapsulatedacyclovir in polymer nanoparticles dispersion gelling sys-tem such as Pluronic F127 is not subjected to topical andtransdermal application only but also nasal and vaginaldeliveries Ramyadevi and Sandhya reported that regardlessof its wide range of particles size distribution (between 68 nmand 1281 nm) the system exhibited reasonable drug loadingcapacity (between 30 and 60) with up to 8 hours ofsustained-release profile In fact both characteristics hadfulfilled the main objective of the study a modified dosageform of acyclovir for delivery to the skin [36] Furtherinvestigations on its in vivo bioavailability would be worthy ofadditional information for the system developed Thereforeintense research and work progress in this area are requiredthat is the toxicity and the stability of the formulationin order to improve the current findings for better andpromising drug delivery methods and preparations

5 Ocular Delivery

Besides topical ointment acyclovir has also been targeted forits ocular delivery Ocular HSV infection occurs when HSVtype 1 infects the sensory neurons of the eye To date herpetickeratitis is one of the most common infectious eye diseases

Journal of Nanomaterials 5

associated with HSV [37] Prolonged herpes keratitis due tolack of treatment or recurrent infection of HSV at the samearea of the cornea would cause dendritic ulcer Eventuallythis event may cause visual impairment or worse blindnessdue to scarring and damage formed in the infected area[38 39]

Acyclovir is not prescribed to patients in the form of eyedrops because of its poor ocular bioavailability and thera-peutic efficacy due to low solubility in water On top of thatdevelopment of drug for delivery to the eye is very challeng-ing There are few factors that need to be taken into consid-eration when designing drug for ocular delivery Eyes havetheir own physical and biological protective mechanismsthat protect them from foreign substances including drugsFor example blinking and tears will reduce andor removeophthalmic drug solution from the conjunctiva There-fore it is quite difficult to get the actual dose of drugto reach the targeted tissue area hence resulting in lowocular drug absorption [40] Treatment of ocular HSV inimmunocompetent patients is prescription of oral acyclovir(800mg daily) andor continuous application of 3 acy-clovir ophthalmic ointment to the cornea area five timesdaily [30 41]

In the last decade a pioneer studywas conducted to inves-tigate the potential of liposome as acyclovir delivery vehicleLiposome offers great advantages as a colloidal drug carrierit is made of biodegradable materials and is nontoxic to cellsBy virtue of that nanosized liposomesmade of phosphatidyl-choline-cholesterol-dimethyl dioctadecyl had been devel-oped to transport acyclovir to the eyes Characteristics ofthe liposomes prepared from different procedures and mem-brane charges were evaluated Data of the study suggestedthat only charged membranes (either positively or negativelycharged liposomes) could interact with acyclovir Negativelycharged liposomes showed the highest drug entrapment effi-ciency when compared with neutral and positively chargedliposomes which could be due to greater aqueous phaseentrapmentwithin the corewhere acyclovir was placedHow-ever only positively charged liposomes showed enhancedocular acyclovir bioavailability in the aqueous humor Thiscould be due to corneal permeability adjustment made byliposomes which allows more drug to enter the cornea area[42]

In agreement with previous study positively chargedliposome was also reported to be bound to and coated onthe corneal surface and enhanced the absorption of acyclovirin the cornea Also longer acyclovir residence time of thepositively charged liposomes was observed in the aqueoushumor of the rabbits due to corneal adhesion as comparedto the commercially available acyclovir ointment [43 44] Insummary a few factors have been discovered to influence theimprovement of acyclovir-liposomes ophthalmic deliverywhich includes rate of corneal permeation and surface chargeof the fabricated liposomes such that it binds to and coats thenegatively charged corneal surface

Besides liposomes poly(ethylene glycol)-co-cyclic acetal(PECA) and polylactic acid (PLA) nanospheres coated withpolyethylene glycol (PEG) with average diameter of 200 nmcould also be a good and suitable drug vehicle for acyclovir

Acyclovir-loaded PECA and PLA nanospheres have demon-strated sustained-release property with mean residence timeof up to 6 hours [45 46] In vivoDraize tests were conductedand findings suggested that nanospheres made from bothtypes of polymer were well tolerated with no eye inflam-mation observed Thus acyclovir-loaded nanospheres wereconsidered safe for ocular use since changes were not seen inthe rabbitrsquos eyes

Acyclovir-loaded PEG coated nanospheres had shown asignificant increase of acyclovir concentration in the aqueoushumor when compared with acyclovir solution These couldhave resulted from higher drug loading capacity and betterocular mucoadhesion of the formulated nanospheres Gooddrug loading capacity and high ocular bioavailability areindication of a successful trial of acyclovir encapsulationfor its ocular delivery Data of the studies suggested thatdrug entrapment efficiency is subjected to environmentand preparation conditions (ie pH and temperature) andtypes and molecular weight of the surfactant and polymerused in the formulation In addition the compositionconcentration and ratio of surfactant and polymer usedin the formulation might influence the physicochemicalproperties of lipid nanoparticles and the ocular tolerabil-ity [47ndash49] Further investigation to test the nanospheresrsquoshelf-life stability will be beneficial for future ocular drugdelivery development

More recently solid lipid nanoparticles have been intro-duced to be a carrier system to deliver poorly water-soluble andor hydrophobic drug It offers many advan-tages over the older colloidal drug delivery systems whichinclude biocompatibility biodegradability and beingmade ofsafenontoxic materials [50 51]Thus as a stable drug carriersolid lipid nanoparticles have been proposed to be a drugvehicle for ophthalmic delivery of acyclovir Acyclovir hasbeen successfully incorporated into solid lipid nanoparticlesmade from glyceryl dibehanate Compritol 888 ATO usingthe modified hot-oil-in-water microemulsion techniqueThemorphology stability and other characteristics of the newlysynthesized nanoparticles were determined before they weretested in excised bovine cornea It was reported that thenegatively charged nanoparticle displayed poor permeationthrough cornea although it exhibited sustained-release profileto supply acyclovir for a longer period of timeHence in orderto overcome the drawback solid lipid nanoparticles havebeen physically converted to nanostructured lipid carriers(400ndash777 nm in diameter) with good drug loading capacitycharacteristic [52]

Besides having good drug entrapment efficiency of up to90 the nanostructured lipid carrier system also enhancedthe acyclovir corneal permeation This has caused an incre-ment of acyclovir cell uptake and its corneal bioavailabilityApart from that chitosan-coated nanostructured lipid carrieralso improved the antiviral efficacy of acyclovir by 35-fold after 24-hour exposure in the cornea of albino rabbitswhen compared with the commercial acyclovir ophthalmicointment available in the market [52 53] The physicochem-ical properties and structures of the formulated solid lipidnanoparticles (ie where acyclovir is loaded in the system)directly influence the bioavailability of acyclovir and rate of

6 Journal of Nanomaterials

corneal permeation as well as its stability These are amongthe important measures for a successful development ofophthalmic drug delivery

6 Conclusion

The development of nanosized drug delivery system forantiviral drugs specifically acyclovir has shown a very goodprogress and high potential to become successful for futurebenefits The delivery of acyclovir through different routes ofadministration in different forms of formulations (ie tabletssuspension and ointment) is substantial in treating patientswith HSV where infection can be mild to one individualbut severe to others depending on their health status Yeteach route of administration has its own disadvantages andside effects Alternative acyclovir delivery system is indeed avery good research area to explore The forthcoming com-mercialization of the end product will be the most excitingpart especially to the pharmaceutical industryNonetheless afew fundamental steps have to be carefully studied before theformulation can be commercializedMoreover it is necessarythat the selection of delivery vehicle for acyclovir be testedvia in vitro and in vivo studies Its optimized therapeuticefficacy and toxicity data can be attained as well as its stabilitytest as a prerequisite for clinical trials Although furtherresearch and studies are required to be performed the currentand up-to-date data from various studies conducted utilisingdifferent methods technology and resources have gainedworldwide attention and thus have contributed importantinformation in this area of research In fact the proposedvehicles have the potential to be commercialized to suitthe current needs for antiviral delivery to overcome itspharmacokinetic drawbacks Research in the nanodeliverysystem for acyclovir will add on to the latest knowledgeand improve our understanding in drug discovery as well asdelivery systems The new technology and system proposedwill not only benefit antiviral drug delivery but also benefitother marketed drugs with similar delivery problems

Competing Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] G B Elion ldquoThe biochemistry and mechanism of action ofacyclovirrdquo Journal of Antimicrobial Chemotherapy vol 12 pp9ndash17 1983

[2] G B Elion ldquoAcyclovir discovery mechanism of action andselectivityrdquo Journal of Medical Virology vol 1 supplement 1 pp2ndash6 1993

[3] J Piret and G Boivin ldquoResistance of herpes simplex viruses tonucleoside analogues mechanisms prevalence and manage-mentrdquo Antimicrobial Agents and Chemotherapy vol 55 no 2pp 459ndash472 2011

[4] J P Smith S Weller B Johnson J Nicotera J M Luther andD W Haas ldquoPharmacokinetics of acyclovir and its metabolites

in cerebrospinal fluid and systemic circulation after adminis-tration of high-dose valacyclovir in subjects with normal andimpaired renal functionrdquo Antimicrobial Agents and Chemother-apy vol 54 no 3 pp 1146ndash1151 2010

[5] R J Whitley M R Blum N Barton and P DeMiranda ldquoPhar-macokinetics of acyclovir in humans following intravenousadministration A model for the development of parenteralantiviralsrdquoThe American Journal of Medicine vol 73 no 1 pp165ndash171 1982

[6] J-M Poirier N Radembino and P Jaillon ldquoDetermination ofacyclovir in plasma by solid-phase extraction and column liquidchromatographyrdquo Therapeutic Drug Monitoring vol 21 no 1pp 129ndash133 1999

[7] M Kubbinga M A Nguyen P Staubach S Teerenstra and PLangguth ldquoThe influence of chitosan on the oral bioavailabilityof acyclovirmdasha comparative bioavailability study in humansrdquoPharmaceutical Research vol 32 no 7 pp 2241ndash2249 2015

[8] A Wald J Benedetti G Davis M Remington C Winterand L Corey ldquoA randomized double-blind comparative trialcomparing high- and standard-dose oral acyclovir for first-episode genital herpes infectionsrdquo Antimicrobial Agents andChemotherapy vol 38 no 2 pp 174ndash176 1994

[9] Y J Bryson M Dillon M Lovett et al ldquoTreatment of firstepisodes of genital herpes simplex virus infection with oral acy-clovir A randomized double-blind controlled trial in normalsubjectsrdquoTheNew England Journal of Medicine vol 308 no 16pp 916ndash921 1983

[10] G W Raborn W T McGaw M Grace L D Tyrrell and SM Samuels ldquoOral acyclovir and herpes labialis a randomizeddouble-blind placebo-controlled studyrdquo The Journal of theAmerican Dental Association vol 115 no 1 pp 38ndash42 1987

[11] H Shirazi M Daneshpour S Kashanian and K OmidfarldquoSynthesis characterization and in vitro biocompatibility studyof AuTMCFe3O4 nanocomposites as a promising nontoxicsystem for biomedical applicationsrdquo Beilstein Journal of Nan-otechnology vol 6 no 1 pp 1677ndash1689 2015

[12] M B Chaudhari P P Desai P A Patel and V B PatravaleldquoSolid lipid nanoparticles of amphotericin B (AmbiOnp) invitro and in vivo assessment towards safe and effective oraltreatment modulerdquo Drug Delivery and Translational Researchvol 6 no 4 pp 354ndash364 2016

[13] Y Oh N Lee H W Kang and J Oh ldquoIn vitro study onapoptotic cell death by effective magnetic hyperthermia withchitosan-coated MnFe2O4rdquo Nanotechnology vol 27 no 11article 115101 2016

[14] B Sapra PThatai S Bhandari J SoodM Jindal andA TiwaryldquoA critical appraisal of microemulsions for drug deliverymdashpartIrdquoTherapeutic Delivery vol 4 no 12 pp 1547ndash1564 2013

[15] D Patel and K K Sawant ldquoOral bioavailability enhancementof acyclovir by self-microemulsifying drug delivery systems(SMEDDS)rdquo Drug Development and Industrial Pharmacy vol33 no 12 pp 1318ndash1326 2007

[16] P KGhosh R JMajithiyaM LUmrethia andR S RMurthyldquoDesign and development of microemulsion drug deliverysystem of acyclovir for improvement of oral bioavailabilityrdquoAAPS PharmSciTech vol 7 no 3 p 77 2006

[17] A Gandhi S Jana and K K Sen ldquoIn-vitro release of acyclovirloaded Eudragit RLPO nanoparticles for sustained drug deliv-eryrdquo International Journal of Biological Macromolecules vol 67pp 478ndash482 2014

[18] S Paul A Kumar P Yedurkar and K Sawant ldquoDesign anddevelopment of multiple emulsion for enhancement of oral

Journal of Nanomaterials 7

bioavailability of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 11 pp 1809ndash1817 2013

[19] B B Ghera F Perret Y Chevalier and H Parrot-LopezldquoNovel nanoparticles made from amphiphilic perfluoroalkyl120572-cyclodextrin derivatives preparation characterization andapplication to the transport of acyclovirrdquo International Journalof Pharmaceutics vol 375 no 1-2 pp 155ndash162 2009

[20] U Sili A Kaya A Mert et al ldquoHerpes simplex virus encephali-tis clinical manifestations diagnosis and outcome in 106 adultpatientsrdquo Journal of Clinical Virology vol 60 no 2 pp 112ndash1182014

[21] X Zhang Y Li H Zhou et al ldquoPlasma metabolic profilinganalysis of nephrotoxicity induced by acyclovir using metabo-nomics coupled with multivariate data analysisrdquo Journal ofPharmaceutical and Biomedical Analysis C vol 97 pp 151ndash1562014

[22] A Seedat and G Winnett ldquoAcyclovir-induced acute renalfailure and the importance of an expanding waist linerdquo BMJCase Reports 2012

[23] H Lu Y-J Han J-D Xu W-M Xing and J Chen ldquoPro-teomic characterization of acyclovir-induced nephrotoxicity ina mouse modelrdquo PLoS ONE vol 9 no 7 Article ID e1031852014

[24] R Fleischer and M Johnson ldquoAcyclovir nephrotoxicity a casereport highlighting the importance of prevention detectionand treatment of acyclovir-induced nephropathyrdquo Case Reportsin Medicine vol 2010 Article ID 602783 3 pages 2010

[25] A O Kamel G A S Awad A S Geneidi and N D MortadaldquoPreparation of intravenous stealthy acyclovir nanoparticleswith increased mean residence timerdquo AAPS PharmSciTech vol10 no 4 pp 1427ndash1436 2009

[26] S Gupta A Agarwal N K Gupta G Saraogi H Agrawal andG P Agrawal ldquoGalactose decorated PLGA nanoparticles forhepatic delivery of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 12 pp 1866ndash1873 2013

[27] Y Jin L Tong P Ai M Li and X Hou ldquoSelf-assembled drugdelivery systems 1 Properties and in vitroin vivo behaviorof acyclovir self-assembled nanoparticles (SAN)rdquo InternationalJournal of Pharmaceutics vol 309 no 1-2 pp 199ndash207 2006

[28] S Rao M J Abzug P Carosone-Link et al ldquoIntravenousacyclovir and renal dysfunction in children A Matched CaseControl Studyrdquo The Journal of Pediatrics vol 166 no 6 pp1462e4ndash1468e4 2015

[29] A B Nair ldquoQuantification of uptake and clearance of acyclovirin skin layersrdquo Antiviral Therapy vol 21 no 1 pp 17ndash25 2015

[30] S Ghosh V Jhanji E Lamoureux H R Taylor and R BVajpayee ldquoAcyclovir therapy in prevention of recurrent herpetickeratitis following penetrating keratoplastyrdquo American Journalof Ophthalmology vol 145 no 2 pp 198ndash202 2008

[31] G E Parry P Dunn V P Shah and L K Pershing ldquoAcyclovirbioavailability in human skinrdquo The Journal of InvestigativeDermatology vol 98 no 6 pp 856ndash863 1992

[32] S A Qureshi M Jiang K K Midha and J P Skelly ldquoInvitro evaluation of percutaneous absorption of an acyclovirproduct using intact and tape-stripped human skinrdquo Journal ofPharmacy amp Pharmaceutical Sciences vol 1 no 3 pp 102ndash1071998

[33] J C Schwarz V Klang S Karall D Mahrhauser G P Reschand C Valenta ldquoOptimisation of multiple WOW nanoemul-sions for dermal delivery of aciclovirrdquo International Journal ofPharmaceutics vol 435 no 1 pp 69ndash75 2012

[34] G Shishu S Rajan and Kamalpreet ldquoDevelopment of novelmicroemulsion-based topical formulations of acyclovir for thetreatment of cutaneous herpetic infectionsrdquo AAPS Pharm-SciTech vol 10 no 2 pp 559ndash565 2009

[35] R Cortesi L Ravani E Menegatti M Drechsler and EEsposito ldquoColloidal dispersions for the delivery of acyclovir AComparative Studyrdquo Indian Journal of Pharmaceutical Sciencesvol 73 no 6 pp 687ndash693 2011

[36] D Ramyadevi and P Sandhya ldquoDual sustained release deliverysystem for multiple route therapy of an antiviral drugrdquo DrugDelivery vol 21 no 4 pp 276ndash292 2014

[37] E Miserocchi G Fogliato I Bianchi F Bandello and GModorati ldquoClinical features of ocular herpetic infection in anItalian referral centerrdquo Cornea vol 33 no 6 pp 565ndash570 2014

[38] S Burrel D Boutolleau G Azar et al ldquoPhenotypic andgenotypic characterization of acyclovir-resistant corneal HSV-1 isolates from immunocompetent patients with recurrentherpetic keratitisrdquo Journal of Clinical Virology vol 58 no 1 pp321ndash324 2013

[39] O Alekseev A H Tran and J Azizkhan-Clifford ldquoEx vivoorganotypic corneal model of acute epithelial herpes simplexvirus type I infectionrdquo Journal of Visualized Experiments no 69Article ID e3631 2012

[40] C Bucolo F Drago and S Salomone ldquoOcular drug deliverya clue from nanotechnologyrdquo Frontiers in Pharmacology vol 3article 188 2012

[41] D D Garcia Q Farjo D C Musch and A Sugar ldquoEffect ofprophylactic oral acyclovir after penetrating keratoplasty forherpes simplex keratitisrdquo Cornea vol 26 no 8 pp 930ndash9342007

[42] M Fresta A M Panico C Bucolo C Giannavola and GPuglisi ldquoCharacterization and in-vivo ocular absorption ofliposome-encapsulated acyclovirrdquoThe Journal of Pharmacy andPharmacology vol 51 no 5 pp 565ndash576 1999

[43] S L Law K J Huang and C H Chiang ldquoAcyclovir-containingliposomes for potential ocular delivery corneal penetration andabsorptionrdquo Journal of Controlled Release vol 63 no 1-2 pp135ndash140 2000

[44] P Chetoni S Rossi S Burgalassi D Monti S Mariotti and MF Saettone ldquoComparison of liposome-encapsulated acyclovirwith acyclovir ointment ocular pharmacokinetics in rabbitsrdquoJournal of Ocular Pharmacology andTherapeutics vol 20 no 2pp 169ndash177 2004

[45] C Giannavola C Bucolo A Maltese et al ldquoInfluence ofpreparation conditions on acyclovir-loaded poly-dl-lactic acidnanospheres and effect of PEG coating on ocular drug bioavail-abilityrdquo Pharmaceutical Research vol 20 no 4 pp 584ndash5902003

[46] M Fresta G Fontana C Bucolo G Cavallaro G Giammonaand G Puglisi ldquoOcular tolerability and in vivo bioavailability ofpoly(ethylene glycol) (PEG)-coated polyethyl-2-cyanoacrylatenanosphere-encapsulated acyclovirrdquo Journal of PharmaceuticalSciences vol 90 no 3 pp 288ndash297 2001

[47] A Leonardi C Bucolo G L Romano et al ldquoInfluence ofdifferent surfactants on the technological properties and in vivoocular tolerability of lipid nanoparticlesrdquo International Journalof Pharmaceutics vol 470 no 1-2 pp 133ndash140 2014

[48] R Pignatello C Bucolo and G Puglisi ldquoOcular tolerability ofEudragit RS100 and RL100 nanosuspensions as carriers forophthalmic controlled drug deliveryrdquo Journal of PharmaceuticalSciences vol 91 no 12 pp 2636ndash2641 2002

8 Journal of Nanomaterials

[49] C Bucolo A Maltese F Maugeri B Busa G Puglisi and RPignatello ldquoEudragit RL100 nanoparticle system for the oph-thalmic delivery of cloricromenerdquoThe Journal of Pharmacy andPharmacology vol 56 no 7 pp 841ndash846 2004

[50] S Misra K Chopra V R Sinha and B Medhi ldquoGalantamine-loaded solidndashlipid nanoparticles for enhanced brain deliverypreparation characterization in vitro and in vivo evaluationsrdquoDrug Delivery vol 23 no 4 pp 1434ndash1443 2016

[51] J Albuquerque C C Moura B Sarmento and S ReisldquoSolid lipid nanoparticles a potential multifunctional approachtowards rheumatoid arthritis theranosticsrdquo Molecules vol 20no 6 pp 11103ndash11118 2015

[52] A Seyfoddin and R Al-Kassas ldquoDevelopment of solid lipidnanoparticles and nanostructured lipid carriers for improvingocular delivery of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 4 pp 508ndash519 2013

[53] A Seyfoddin T Sherwin D V Patel et al ldquoEx vivo and in vivoevaluation of chitosan coated nanostructured lipid carriers forocular delivery of acyclovirrdquo Current Drug Delivery In press

Submit your manuscripts athttpwwwhindawicom

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CorrosionInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Polymer ScienceInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CeramicsJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CompositesJournal of

NanoparticlesJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Biomaterials

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

NanoscienceJournal of

TextilesHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Journal of

NanotechnologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

CrystallographyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CoatingsJournal of

Advances in

Materials Science and EngineeringHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Smart Materials Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MetallurgyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

MaterialsJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Nano

materials

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal ofNanomaterials

Journal of Nanomaterials 5

associated with HSV [37] Prolonged herpes keratitis due tolack of treatment or recurrent infection of HSV at the samearea of the cornea would cause dendritic ulcer Eventuallythis event may cause visual impairment or worse blindnessdue to scarring and damage formed in the infected area[38 39]

Acyclovir is not prescribed to patients in the form of eyedrops because of its poor ocular bioavailability and thera-peutic efficacy due to low solubility in water On top of thatdevelopment of drug for delivery to the eye is very challeng-ing There are few factors that need to be taken into consid-eration when designing drug for ocular delivery Eyes havetheir own physical and biological protective mechanismsthat protect them from foreign substances including drugsFor example blinking and tears will reduce andor removeophthalmic drug solution from the conjunctiva There-fore it is quite difficult to get the actual dose of drugto reach the targeted tissue area hence resulting in lowocular drug absorption [40] Treatment of ocular HSV inimmunocompetent patients is prescription of oral acyclovir(800mg daily) andor continuous application of 3 acy-clovir ophthalmic ointment to the cornea area five timesdaily [30 41]

In the last decade a pioneer studywas conducted to inves-tigate the potential of liposome as acyclovir delivery vehicleLiposome offers great advantages as a colloidal drug carrierit is made of biodegradable materials and is nontoxic to cellsBy virtue of that nanosized liposomesmade of phosphatidyl-choline-cholesterol-dimethyl dioctadecyl had been devel-oped to transport acyclovir to the eyes Characteristics ofthe liposomes prepared from different procedures and mem-brane charges were evaluated Data of the study suggestedthat only charged membranes (either positively or negativelycharged liposomes) could interact with acyclovir Negativelycharged liposomes showed the highest drug entrapment effi-ciency when compared with neutral and positively chargedliposomes which could be due to greater aqueous phaseentrapmentwithin the corewhere acyclovir was placedHow-ever only positively charged liposomes showed enhancedocular acyclovir bioavailability in the aqueous humor Thiscould be due to corneal permeability adjustment made byliposomes which allows more drug to enter the cornea area[42]

In agreement with previous study positively chargedliposome was also reported to be bound to and coated onthe corneal surface and enhanced the absorption of acyclovirin the cornea Also longer acyclovir residence time of thepositively charged liposomes was observed in the aqueoushumor of the rabbits due to corneal adhesion as comparedto the commercially available acyclovir ointment [43 44] Insummary a few factors have been discovered to influence theimprovement of acyclovir-liposomes ophthalmic deliverywhich includes rate of corneal permeation and surface chargeof the fabricated liposomes such that it binds to and coats thenegatively charged corneal surface

Besides liposomes poly(ethylene glycol)-co-cyclic acetal(PECA) and polylactic acid (PLA) nanospheres coated withpolyethylene glycol (PEG) with average diameter of 200 nmcould also be a good and suitable drug vehicle for acyclovir

Acyclovir-loaded PECA and PLA nanospheres have demon-strated sustained-release property with mean residence timeof up to 6 hours [45 46] In vivoDraize tests were conductedand findings suggested that nanospheres made from bothtypes of polymer were well tolerated with no eye inflam-mation observed Thus acyclovir-loaded nanospheres wereconsidered safe for ocular use since changes were not seen inthe rabbitrsquos eyes

Acyclovir-loaded PEG coated nanospheres had shown asignificant increase of acyclovir concentration in the aqueoushumor when compared with acyclovir solution These couldhave resulted from higher drug loading capacity and betterocular mucoadhesion of the formulated nanospheres Gooddrug loading capacity and high ocular bioavailability areindication of a successful trial of acyclovir encapsulationfor its ocular delivery Data of the studies suggested thatdrug entrapment efficiency is subjected to environmentand preparation conditions (ie pH and temperature) andtypes and molecular weight of the surfactant and polymerused in the formulation In addition the compositionconcentration and ratio of surfactant and polymer usedin the formulation might influence the physicochemicalproperties of lipid nanoparticles and the ocular tolerabil-ity [47ndash49] Further investigation to test the nanospheresrsquoshelf-life stability will be beneficial for future ocular drugdelivery development

More recently solid lipid nanoparticles have been intro-duced to be a carrier system to deliver poorly water-soluble andor hydrophobic drug It offers many advan-tages over the older colloidal drug delivery systems whichinclude biocompatibility biodegradability and beingmade ofsafenontoxic materials [50 51]Thus as a stable drug carriersolid lipid nanoparticles have been proposed to be a drugvehicle for ophthalmic delivery of acyclovir Acyclovir hasbeen successfully incorporated into solid lipid nanoparticlesmade from glyceryl dibehanate Compritol 888 ATO usingthe modified hot-oil-in-water microemulsion techniqueThemorphology stability and other characteristics of the newlysynthesized nanoparticles were determined before they weretested in excised bovine cornea It was reported that thenegatively charged nanoparticle displayed poor permeationthrough cornea although it exhibited sustained-release profileto supply acyclovir for a longer period of timeHence in orderto overcome the drawback solid lipid nanoparticles havebeen physically converted to nanostructured lipid carriers(400ndash777 nm in diameter) with good drug loading capacitycharacteristic [52]

Besides having good drug entrapment efficiency of up to90 the nanostructured lipid carrier system also enhancedthe acyclovir corneal permeation This has caused an incre-ment of acyclovir cell uptake and its corneal bioavailabilityApart from that chitosan-coated nanostructured lipid carrieralso improved the antiviral efficacy of acyclovir by 35-fold after 24-hour exposure in the cornea of albino rabbitswhen compared with the commercial acyclovir ophthalmicointment available in the market [52 53] The physicochem-ical properties and structures of the formulated solid lipidnanoparticles (ie where acyclovir is loaded in the system)directly influence the bioavailability of acyclovir and rate of

6 Journal of Nanomaterials

corneal permeation as well as its stability These are amongthe important measures for a successful development ofophthalmic drug delivery

6 Conclusion

The development of nanosized drug delivery system forantiviral drugs specifically acyclovir has shown a very goodprogress and high potential to become successful for futurebenefits The delivery of acyclovir through different routes ofadministration in different forms of formulations (ie tabletssuspension and ointment) is substantial in treating patientswith HSV where infection can be mild to one individualbut severe to others depending on their health status Yeteach route of administration has its own disadvantages andside effects Alternative acyclovir delivery system is indeed avery good research area to explore The forthcoming com-mercialization of the end product will be the most excitingpart especially to the pharmaceutical industryNonetheless afew fundamental steps have to be carefully studied before theformulation can be commercializedMoreover it is necessarythat the selection of delivery vehicle for acyclovir be testedvia in vitro and in vivo studies Its optimized therapeuticefficacy and toxicity data can be attained as well as its stabilitytest as a prerequisite for clinical trials Although furtherresearch and studies are required to be performed the currentand up-to-date data from various studies conducted utilisingdifferent methods technology and resources have gainedworldwide attention and thus have contributed importantinformation in this area of research In fact the proposedvehicles have the potential to be commercialized to suitthe current needs for antiviral delivery to overcome itspharmacokinetic drawbacks Research in the nanodeliverysystem for acyclovir will add on to the latest knowledgeand improve our understanding in drug discovery as well asdelivery systems The new technology and system proposedwill not only benefit antiviral drug delivery but also benefitother marketed drugs with similar delivery problems

Competing Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] G B Elion ldquoThe biochemistry and mechanism of action ofacyclovirrdquo Journal of Antimicrobial Chemotherapy vol 12 pp9ndash17 1983

[2] G B Elion ldquoAcyclovir discovery mechanism of action andselectivityrdquo Journal of Medical Virology vol 1 supplement 1 pp2ndash6 1993

[3] J Piret and G Boivin ldquoResistance of herpes simplex viruses tonucleoside analogues mechanisms prevalence and manage-mentrdquo Antimicrobial Agents and Chemotherapy vol 55 no 2pp 459ndash472 2011

[4] J P Smith S Weller B Johnson J Nicotera J M Luther andD W Haas ldquoPharmacokinetics of acyclovir and its metabolites

in cerebrospinal fluid and systemic circulation after adminis-tration of high-dose valacyclovir in subjects with normal andimpaired renal functionrdquo Antimicrobial Agents and Chemother-apy vol 54 no 3 pp 1146ndash1151 2010

[5] R J Whitley M R Blum N Barton and P DeMiranda ldquoPhar-macokinetics of acyclovir in humans following intravenousadministration A model for the development of parenteralantiviralsrdquoThe American Journal of Medicine vol 73 no 1 pp165ndash171 1982

[6] J-M Poirier N Radembino and P Jaillon ldquoDetermination ofacyclovir in plasma by solid-phase extraction and column liquidchromatographyrdquo Therapeutic Drug Monitoring vol 21 no 1pp 129ndash133 1999

[7] M Kubbinga M A Nguyen P Staubach S Teerenstra and PLangguth ldquoThe influence of chitosan on the oral bioavailabilityof acyclovirmdasha comparative bioavailability study in humansrdquoPharmaceutical Research vol 32 no 7 pp 2241ndash2249 2015

[8] A Wald J Benedetti G Davis M Remington C Winterand L Corey ldquoA randomized double-blind comparative trialcomparing high- and standard-dose oral acyclovir for first-episode genital herpes infectionsrdquo Antimicrobial Agents andChemotherapy vol 38 no 2 pp 174ndash176 1994

[9] Y J Bryson M Dillon M Lovett et al ldquoTreatment of firstepisodes of genital herpes simplex virus infection with oral acy-clovir A randomized double-blind controlled trial in normalsubjectsrdquoTheNew England Journal of Medicine vol 308 no 16pp 916ndash921 1983

[10] G W Raborn W T McGaw M Grace L D Tyrrell and SM Samuels ldquoOral acyclovir and herpes labialis a randomizeddouble-blind placebo-controlled studyrdquo The Journal of theAmerican Dental Association vol 115 no 1 pp 38ndash42 1987

[11] H Shirazi M Daneshpour S Kashanian and K OmidfarldquoSynthesis characterization and in vitro biocompatibility studyof AuTMCFe3O4 nanocomposites as a promising nontoxicsystem for biomedical applicationsrdquo Beilstein Journal of Nan-otechnology vol 6 no 1 pp 1677ndash1689 2015

[12] M B Chaudhari P P Desai P A Patel and V B PatravaleldquoSolid lipid nanoparticles of amphotericin B (AmbiOnp) invitro and in vivo assessment towards safe and effective oraltreatment modulerdquo Drug Delivery and Translational Researchvol 6 no 4 pp 354ndash364 2016

[13] Y Oh N Lee H W Kang and J Oh ldquoIn vitro study onapoptotic cell death by effective magnetic hyperthermia withchitosan-coated MnFe2O4rdquo Nanotechnology vol 27 no 11article 115101 2016

[14] B Sapra PThatai S Bhandari J SoodM Jindal andA TiwaryldquoA critical appraisal of microemulsions for drug deliverymdashpartIrdquoTherapeutic Delivery vol 4 no 12 pp 1547ndash1564 2013

[15] D Patel and K K Sawant ldquoOral bioavailability enhancementof acyclovir by self-microemulsifying drug delivery systems(SMEDDS)rdquo Drug Development and Industrial Pharmacy vol33 no 12 pp 1318ndash1326 2007

[16] P KGhosh R JMajithiyaM LUmrethia andR S RMurthyldquoDesign and development of microemulsion drug deliverysystem of acyclovir for improvement of oral bioavailabilityrdquoAAPS PharmSciTech vol 7 no 3 p 77 2006

[17] A Gandhi S Jana and K K Sen ldquoIn-vitro release of acyclovirloaded Eudragit RLPO nanoparticles for sustained drug deliv-eryrdquo International Journal of Biological Macromolecules vol 67pp 478ndash482 2014

[18] S Paul A Kumar P Yedurkar and K Sawant ldquoDesign anddevelopment of multiple emulsion for enhancement of oral

Journal of Nanomaterials 7

bioavailability of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 11 pp 1809ndash1817 2013

[19] B B Ghera F Perret Y Chevalier and H Parrot-LopezldquoNovel nanoparticles made from amphiphilic perfluoroalkyl120572-cyclodextrin derivatives preparation characterization andapplication to the transport of acyclovirrdquo International Journalof Pharmaceutics vol 375 no 1-2 pp 155ndash162 2009

[20] U Sili A Kaya A Mert et al ldquoHerpes simplex virus encephali-tis clinical manifestations diagnosis and outcome in 106 adultpatientsrdquo Journal of Clinical Virology vol 60 no 2 pp 112ndash1182014

[21] X Zhang Y Li H Zhou et al ldquoPlasma metabolic profilinganalysis of nephrotoxicity induced by acyclovir using metabo-nomics coupled with multivariate data analysisrdquo Journal ofPharmaceutical and Biomedical Analysis C vol 97 pp 151ndash1562014

[22] A Seedat and G Winnett ldquoAcyclovir-induced acute renalfailure and the importance of an expanding waist linerdquo BMJCase Reports 2012

[23] H Lu Y-J Han J-D Xu W-M Xing and J Chen ldquoPro-teomic characterization of acyclovir-induced nephrotoxicity ina mouse modelrdquo PLoS ONE vol 9 no 7 Article ID e1031852014

[24] R Fleischer and M Johnson ldquoAcyclovir nephrotoxicity a casereport highlighting the importance of prevention detectionand treatment of acyclovir-induced nephropathyrdquo Case Reportsin Medicine vol 2010 Article ID 602783 3 pages 2010

[25] A O Kamel G A S Awad A S Geneidi and N D MortadaldquoPreparation of intravenous stealthy acyclovir nanoparticleswith increased mean residence timerdquo AAPS PharmSciTech vol10 no 4 pp 1427ndash1436 2009

[26] S Gupta A Agarwal N K Gupta G Saraogi H Agrawal andG P Agrawal ldquoGalactose decorated PLGA nanoparticles forhepatic delivery of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 12 pp 1866ndash1873 2013

[27] Y Jin L Tong P Ai M Li and X Hou ldquoSelf-assembled drugdelivery systems 1 Properties and in vitroin vivo behaviorof acyclovir self-assembled nanoparticles (SAN)rdquo InternationalJournal of Pharmaceutics vol 309 no 1-2 pp 199ndash207 2006

[28] S Rao M J Abzug P Carosone-Link et al ldquoIntravenousacyclovir and renal dysfunction in children A Matched CaseControl Studyrdquo The Journal of Pediatrics vol 166 no 6 pp1462e4ndash1468e4 2015

[29] A B Nair ldquoQuantification of uptake and clearance of acyclovirin skin layersrdquo Antiviral Therapy vol 21 no 1 pp 17ndash25 2015

[30] S Ghosh V Jhanji E Lamoureux H R Taylor and R BVajpayee ldquoAcyclovir therapy in prevention of recurrent herpetickeratitis following penetrating keratoplastyrdquo American Journalof Ophthalmology vol 145 no 2 pp 198ndash202 2008

[31] G E Parry P Dunn V P Shah and L K Pershing ldquoAcyclovirbioavailability in human skinrdquo The Journal of InvestigativeDermatology vol 98 no 6 pp 856ndash863 1992

[32] S A Qureshi M Jiang K K Midha and J P Skelly ldquoInvitro evaluation of percutaneous absorption of an acyclovirproduct using intact and tape-stripped human skinrdquo Journal ofPharmacy amp Pharmaceutical Sciences vol 1 no 3 pp 102ndash1071998

[33] J C Schwarz V Klang S Karall D Mahrhauser G P Reschand C Valenta ldquoOptimisation of multiple WOW nanoemul-sions for dermal delivery of aciclovirrdquo International Journal ofPharmaceutics vol 435 no 1 pp 69ndash75 2012

[34] G Shishu S Rajan and Kamalpreet ldquoDevelopment of novelmicroemulsion-based topical formulations of acyclovir for thetreatment of cutaneous herpetic infectionsrdquo AAPS Pharm-SciTech vol 10 no 2 pp 559ndash565 2009

[35] R Cortesi L Ravani E Menegatti M Drechsler and EEsposito ldquoColloidal dispersions for the delivery of acyclovir AComparative Studyrdquo Indian Journal of Pharmaceutical Sciencesvol 73 no 6 pp 687ndash693 2011

[36] D Ramyadevi and P Sandhya ldquoDual sustained release deliverysystem for multiple route therapy of an antiviral drugrdquo DrugDelivery vol 21 no 4 pp 276ndash292 2014

[37] E Miserocchi G Fogliato I Bianchi F Bandello and GModorati ldquoClinical features of ocular herpetic infection in anItalian referral centerrdquo Cornea vol 33 no 6 pp 565ndash570 2014

[38] S Burrel D Boutolleau G Azar et al ldquoPhenotypic andgenotypic characterization of acyclovir-resistant corneal HSV-1 isolates from immunocompetent patients with recurrentherpetic keratitisrdquo Journal of Clinical Virology vol 58 no 1 pp321ndash324 2013

[39] O Alekseev A H Tran and J Azizkhan-Clifford ldquoEx vivoorganotypic corneal model of acute epithelial herpes simplexvirus type I infectionrdquo Journal of Visualized Experiments no 69Article ID e3631 2012

[40] C Bucolo F Drago and S Salomone ldquoOcular drug deliverya clue from nanotechnologyrdquo Frontiers in Pharmacology vol 3article 188 2012

[41] D D Garcia Q Farjo D C Musch and A Sugar ldquoEffect ofprophylactic oral acyclovir after penetrating keratoplasty forherpes simplex keratitisrdquo Cornea vol 26 no 8 pp 930ndash9342007

[42] M Fresta A M Panico C Bucolo C Giannavola and GPuglisi ldquoCharacterization and in-vivo ocular absorption ofliposome-encapsulated acyclovirrdquoThe Journal of Pharmacy andPharmacology vol 51 no 5 pp 565ndash576 1999

[43] S L Law K J Huang and C H Chiang ldquoAcyclovir-containingliposomes for potential ocular delivery corneal penetration andabsorptionrdquo Journal of Controlled Release vol 63 no 1-2 pp135ndash140 2000

[44] P Chetoni S Rossi S Burgalassi D Monti S Mariotti and MF Saettone ldquoComparison of liposome-encapsulated acyclovirwith acyclovir ointment ocular pharmacokinetics in rabbitsrdquoJournal of Ocular Pharmacology andTherapeutics vol 20 no 2pp 169ndash177 2004

[45] C Giannavola C Bucolo A Maltese et al ldquoInfluence ofpreparation conditions on acyclovir-loaded poly-dl-lactic acidnanospheres and effect of PEG coating on ocular drug bioavail-abilityrdquo Pharmaceutical Research vol 20 no 4 pp 584ndash5902003

[46] M Fresta G Fontana C Bucolo G Cavallaro G Giammonaand G Puglisi ldquoOcular tolerability and in vivo bioavailability ofpoly(ethylene glycol) (PEG)-coated polyethyl-2-cyanoacrylatenanosphere-encapsulated acyclovirrdquo Journal of PharmaceuticalSciences vol 90 no 3 pp 288ndash297 2001

[47] A Leonardi C Bucolo G L Romano et al ldquoInfluence ofdifferent surfactants on the technological properties and in vivoocular tolerability of lipid nanoparticlesrdquo International Journalof Pharmaceutics vol 470 no 1-2 pp 133ndash140 2014

[48] R Pignatello C Bucolo and G Puglisi ldquoOcular tolerability ofEudragit RS100 and RL100 nanosuspensions as carriers forophthalmic controlled drug deliveryrdquo Journal of PharmaceuticalSciences vol 91 no 12 pp 2636ndash2641 2002

8 Journal of Nanomaterials

[49] C Bucolo A Maltese F Maugeri B Busa G Puglisi and RPignatello ldquoEudragit RL100 nanoparticle system for the oph-thalmic delivery of cloricromenerdquoThe Journal of Pharmacy andPharmacology vol 56 no 7 pp 841ndash846 2004

[50] S Misra K Chopra V R Sinha and B Medhi ldquoGalantamine-loaded solidndashlipid nanoparticles for enhanced brain deliverypreparation characterization in vitro and in vivo evaluationsrdquoDrug Delivery vol 23 no 4 pp 1434ndash1443 2016

[51] J Albuquerque C C Moura B Sarmento and S ReisldquoSolid lipid nanoparticles a potential multifunctional approachtowards rheumatoid arthritis theranosticsrdquo Molecules vol 20no 6 pp 11103ndash11118 2015

[52] A Seyfoddin and R Al-Kassas ldquoDevelopment of solid lipidnanoparticles and nanostructured lipid carriers for improvingocular delivery of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 4 pp 508ndash519 2013

[53] A Seyfoddin T Sherwin D V Patel et al ldquoEx vivo and in vivoevaluation of chitosan coated nanostructured lipid carriers forocular delivery of acyclovirrdquo Current Drug Delivery In press

Submit your manuscripts athttpwwwhindawicom

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CorrosionInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Polymer ScienceInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CeramicsJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CompositesJournal of

NanoparticlesJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Biomaterials

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

NanoscienceJournal of

TextilesHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Journal of

NanotechnologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

CrystallographyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CoatingsJournal of

Advances in

Materials Science and EngineeringHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Smart Materials Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MetallurgyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

MaterialsJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Nano

materials

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal ofNanomaterials

6 Journal of Nanomaterials

corneal permeation as well as its stability These are amongthe important measures for a successful development ofophthalmic drug delivery

6 Conclusion

The development of nanosized drug delivery system forantiviral drugs specifically acyclovir has shown a very goodprogress and high potential to become successful for futurebenefits The delivery of acyclovir through different routes ofadministration in different forms of formulations (ie tabletssuspension and ointment) is substantial in treating patientswith HSV where infection can be mild to one individualbut severe to others depending on their health status Yeteach route of administration has its own disadvantages andside effects Alternative acyclovir delivery system is indeed avery good research area to explore The forthcoming com-mercialization of the end product will be the most excitingpart especially to the pharmaceutical industryNonetheless afew fundamental steps have to be carefully studied before theformulation can be commercializedMoreover it is necessarythat the selection of delivery vehicle for acyclovir be testedvia in vitro and in vivo studies Its optimized therapeuticefficacy and toxicity data can be attained as well as its stabilitytest as a prerequisite for clinical trials Although furtherresearch and studies are required to be performed the currentand up-to-date data from various studies conducted utilisingdifferent methods technology and resources have gainedworldwide attention and thus have contributed importantinformation in this area of research In fact the proposedvehicles have the potential to be commercialized to suitthe current needs for antiviral delivery to overcome itspharmacokinetic drawbacks Research in the nanodeliverysystem for acyclovir will add on to the latest knowledgeand improve our understanding in drug discovery as well asdelivery systems The new technology and system proposedwill not only benefit antiviral drug delivery but also benefitother marketed drugs with similar delivery problems

Competing Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] G B Elion ldquoThe biochemistry and mechanism of action ofacyclovirrdquo Journal of Antimicrobial Chemotherapy vol 12 pp9ndash17 1983

[2] G B Elion ldquoAcyclovir discovery mechanism of action andselectivityrdquo Journal of Medical Virology vol 1 supplement 1 pp2ndash6 1993

[3] J Piret and G Boivin ldquoResistance of herpes simplex viruses tonucleoside analogues mechanisms prevalence and manage-mentrdquo Antimicrobial Agents and Chemotherapy vol 55 no 2pp 459ndash472 2011

[4] J P Smith S Weller B Johnson J Nicotera J M Luther andD W Haas ldquoPharmacokinetics of acyclovir and its metabolites

in cerebrospinal fluid and systemic circulation after adminis-tration of high-dose valacyclovir in subjects with normal andimpaired renal functionrdquo Antimicrobial Agents and Chemother-apy vol 54 no 3 pp 1146ndash1151 2010

[5] R J Whitley M R Blum N Barton and P DeMiranda ldquoPhar-macokinetics of acyclovir in humans following intravenousadministration A model for the development of parenteralantiviralsrdquoThe American Journal of Medicine vol 73 no 1 pp165ndash171 1982

[6] J-M Poirier N Radembino and P Jaillon ldquoDetermination ofacyclovir in plasma by solid-phase extraction and column liquidchromatographyrdquo Therapeutic Drug Monitoring vol 21 no 1pp 129ndash133 1999

[7] M Kubbinga M A Nguyen P Staubach S Teerenstra and PLangguth ldquoThe influence of chitosan on the oral bioavailabilityof acyclovirmdasha comparative bioavailability study in humansrdquoPharmaceutical Research vol 32 no 7 pp 2241ndash2249 2015

[8] A Wald J Benedetti G Davis M Remington C Winterand L Corey ldquoA randomized double-blind comparative trialcomparing high- and standard-dose oral acyclovir for first-episode genital herpes infectionsrdquo Antimicrobial Agents andChemotherapy vol 38 no 2 pp 174ndash176 1994

[9] Y J Bryson M Dillon M Lovett et al ldquoTreatment of firstepisodes of genital herpes simplex virus infection with oral acy-clovir A randomized double-blind controlled trial in normalsubjectsrdquoTheNew England Journal of Medicine vol 308 no 16pp 916ndash921 1983

[10] G W Raborn W T McGaw M Grace L D Tyrrell and SM Samuels ldquoOral acyclovir and herpes labialis a randomizeddouble-blind placebo-controlled studyrdquo The Journal of theAmerican Dental Association vol 115 no 1 pp 38ndash42 1987

[11] H Shirazi M Daneshpour S Kashanian and K OmidfarldquoSynthesis characterization and in vitro biocompatibility studyof AuTMCFe3O4 nanocomposites as a promising nontoxicsystem for biomedical applicationsrdquo Beilstein Journal of Nan-otechnology vol 6 no 1 pp 1677ndash1689 2015

[12] M B Chaudhari P P Desai P A Patel and V B PatravaleldquoSolid lipid nanoparticles of amphotericin B (AmbiOnp) invitro and in vivo assessment towards safe and effective oraltreatment modulerdquo Drug Delivery and Translational Researchvol 6 no 4 pp 354ndash364 2016

[13] Y Oh N Lee H W Kang and J Oh ldquoIn vitro study onapoptotic cell death by effective magnetic hyperthermia withchitosan-coated MnFe2O4rdquo Nanotechnology vol 27 no 11article 115101 2016

[14] B Sapra PThatai S Bhandari J SoodM Jindal andA TiwaryldquoA critical appraisal of microemulsions for drug deliverymdashpartIrdquoTherapeutic Delivery vol 4 no 12 pp 1547ndash1564 2013

[15] D Patel and K K Sawant ldquoOral bioavailability enhancementof acyclovir by self-microemulsifying drug delivery systems(SMEDDS)rdquo Drug Development and Industrial Pharmacy vol33 no 12 pp 1318ndash1326 2007

[16] P KGhosh R JMajithiyaM LUmrethia andR S RMurthyldquoDesign and development of microemulsion drug deliverysystem of acyclovir for improvement of oral bioavailabilityrdquoAAPS PharmSciTech vol 7 no 3 p 77 2006

[17] A Gandhi S Jana and K K Sen ldquoIn-vitro release of acyclovirloaded Eudragit RLPO nanoparticles for sustained drug deliv-eryrdquo International Journal of Biological Macromolecules vol 67pp 478ndash482 2014

[18] S Paul A Kumar P Yedurkar and K Sawant ldquoDesign anddevelopment of multiple emulsion for enhancement of oral

Journal of Nanomaterials 7

bioavailability of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 11 pp 1809ndash1817 2013

[19] B B Ghera F Perret Y Chevalier and H Parrot-LopezldquoNovel nanoparticles made from amphiphilic perfluoroalkyl120572-cyclodextrin derivatives preparation characterization andapplication to the transport of acyclovirrdquo International Journalof Pharmaceutics vol 375 no 1-2 pp 155ndash162 2009

[20] U Sili A Kaya A Mert et al ldquoHerpes simplex virus encephali-tis clinical manifestations diagnosis and outcome in 106 adultpatientsrdquo Journal of Clinical Virology vol 60 no 2 pp 112ndash1182014

[21] X Zhang Y Li H Zhou et al ldquoPlasma metabolic profilinganalysis of nephrotoxicity induced by acyclovir using metabo-nomics coupled with multivariate data analysisrdquo Journal ofPharmaceutical and Biomedical Analysis C vol 97 pp 151ndash1562014

[22] A Seedat and G Winnett ldquoAcyclovir-induced acute renalfailure and the importance of an expanding waist linerdquo BMJCase Reports 2012

[23] H Lu Y-J Han J-D Xu W-M Xing and J Chen ldquoPro-teomic characterization of acyclovir-induced nephrotoxicity ina mouse modelrdquo PLoS ONE vol 9 no 7 Article ID e1031852014

[24] R Fleischer and M Johnson ldquoAcyclovir nephrotoxicity a casereport highlighting the importance of prevention detectionand treatment of acyclovir-induced nephropathyrdquo Case Reportsin Medicine vol 2010 Article ID 602783 3 pages 2010

[25] A O Kamel G A S Awad A S Geneidi and N D MortadaldquoPreparation of intravenous stealthy acyclovir nanoparticleswith increased mean residence timerdquo AAPS PharmSciTech vol10 no 4 pp 1427ndash1436 2009

[26] S Gupta A Agarwal N K Gupta G Saraogi H Agrawal andG P Agrawal ldquoGalactose decorated PLGA nanoparticles forhepatic delivery of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 12 pp 1866ndash1873 2013

[27] Y Jin L Tong P Ai M Li and X Hou ldquoSelf-assembled drugdelivery systems 1 Properties and in vitroin vivo behaviorof acyclovir self-assembled nanoparticles (SAN)rdquo InternationalJournal of Pharmaceutics vol 309 no 1-2 pp 199ndash207 2006

[28] S Rao M J Abzug P Carosone-Link et al ldquoIntravenousacyclovir and renal dysfunction in children A Matched CaseControl Studyrdquo The Journal of Pediatrics vol 166 no 6 pp1462e4ndash1468e4 2015

[29] A B Nair ldquoQuantification of uptake and clearance of acyclovirin skin layersrdquo Antiviral Therapy vol 21 no 1 pp 17ndash25 2015

[30] S Ghosh V Jhanji E Lamoureux H R Taylor and R BVajpayee ldquoAcyclovir therapy in prevention of recurrent herpetickeratitis following penetrating keratoplastyrdquo American Journalof Ophthalmology vol 145 no 2 pp 198ndash202 2008

[31] G E Parry P Dunn V P Shah and L K Pershing ldquoAcyclovirbioavailability in human skinrdquo The Journal of InvestigativeDermatology vol 98 no 6 pp 856ndash863 1992

[32] S A Qureshi M Jiang K K Midha and J P Skelly ldquoInvitro evaluation of percutaneous absorption of an acyclovirproduct using intact and tape-stripped human skinrdquo Journal ofPharmacy amp Pharmaceutical Sciences vol 1 no 3 pp 102ndash1071998

[33] J C Schwarz V Klang S Karall D Mahrhauser G P Reschand C Valenta ldquoOptimisation of multiple WOW nanoemul-sions for dermal delivery of aciclovirrdquo International Journal ofPharmaceutics vol 435 no 1 pp 69ndash75 2012

[34] G Shishu S Rajan and Kamalpreet ldquoDevelopment of novelmicroemulsion-based topical formulations of acyclovir for thetreatment of cutaneous herpetic infectionsrdquo AAPS Pharm-SciTech vol 10 no 2 pp 559ndash565 2009

[35] R Cortesi L Ravani E Menegatti M Drechsler and EEsposito ldquoColloidal dispersions for the delivery of acyclovir AComparative Studyrdquo Indian Journal of Pharmaceutical Sciencesvol 73 no 6 pp 687ndash693 2011

[36] D Ramyadevi and P Sandhya ldquoDual sustained release deliverysystem for multiple route therapy of an antiviral drugrdquo DrugDelivery vol 21 no 4 pp 276ndash292 2014

[37] E Miserocchi G Fogliato I Bianchi F Bandello and GModorati ldquoClinical features of ocular herpetic infection in anItalian referral centerrdquo Cornea vol 33 no 6 pp 565ndash570 2014

[38] S Burrel D Boutolleau G Azar et al ldquoPhenotypic andgenotypic characterization of acyclovir-resistant corneal HSV-1 isolates from immunocompetent patients with recurrentherpetic keratitisrdquo Journal of Clinical Virology vol 58 no 1 pp321ndash324 2013

[39] O Alekseev A H Tran and J Azizkhan-Clifford ldquoEx vivoorganotypic corneal model of acute epithelial herpes simplexvirus type I infectionrdquo Journal of Visualized Experiments no 69Article ID e3631 2012

[40] C Bucolo F Drago and S Salomone ldquoOcular drug deliverya clue from nanotechnologyrdquo Frontiers in Pharmacology vol 3article 188 2012

[41] D D Garcia Q Farjo D C Musch and A Sugar ldquoEffect ofprophylactic oral acyclovir after penetrating keratoplasty forherpes simplex keratitisrdquo Cornea vol 26 no 8 pp 930ndash9342007

[42] M Fresta A M Panico C Bucolo C Giannavola and GPuglisi ldquoCharacterization and in-vivo ocular absorption ofliposome-encapsulated acyclovirrdquoThe Journal of Pharmacy andPharmacology vol 51 no 5 pp 565ndash576 1999

[43] S L Law K J Huang and C H Chiang ldquoAcyclovir-containingliposomes for potential ocular delivery corneal penetration andabsorptionrdquo Journal of Controlled Release vol 63 no 1-2 pp135ndash140 2000

[44] P Chetoni S Rossi S Burgalassi D Monti S Mariotti and MF Saettone ldquoComparison of liposome-encapsulated acyclovirwith acyclovir ointment ocular pharmacokinetics in rabbitsrdquoJournal of Ocular Pharmacology andTherapeutics vol 20 no 2pp 169ndash177 2004

[45] C Giannavola C Bucolo A Maltese et al ldquoInfluence ofpreparation conditions on acyclovir-loaded poly-dl-lactic acidnanospheres and effect of PEG coating on ocular drug bioavail-abilityrdquo Pharmaceutical Research vol 20 no 4 pp 584ndash5902003

[46] M Fresta G Fontana C Bucolo G Cavallaro G Giammonaand G Puglisi ldquoOcular tolerability and in vivo bioavailability ofpoly(ethylene glycol) (PEG)-coated polyethyl-2-cyanoacrylatenanosphere-encapsulated acyclovirrdquo Journal of PharmaceuticalSciences vol 90 no 3 pp 288ndash297 2001

[47] A Leonardi C Bucolo G L Romano et al ldquoInfluence ofdifferent surfactants on the technological properties and in vivoocular tolerability of lipid nanoparticlesrdquo International Journalof Pharmaceutics vol 470 no 1-2 pp 133ndash140 2014

[48] R Pignatello C Bucolo and G Puglisi ldquoOcular tolerability ofEudragit RS100 and RL100 nanosuspensions as carriers forophthalmic controlled drug deliveryrdquo Journal of PharmaceuticalSciences vol 91 no 12 pp 2636ndash2641 2002

8 Journal of Nanomaterials

[49] C Bucolo A Maltese F Maugeri B Busa G Puglisi and RPignatello ldquoEudragit RL100 nanoparticle system for the oph-thalmic delivery of cloricromenerdquoThe Journal of Pharmacy andPharmacology vol 56 no 7 pp 841ndash846 2004

[50] S Misra K Chopra V R Sinha and B Medhi ldquoGalantamine-loaded solidndashlipid nanoparticles for enhanced brain deliverypreparation characterization in vitro and in vivo evaluationsrdquoDrug Delivery vol 23 no 4 pp 1434ndash1443 2016

[51] J Albuquerque C C Moura B Sarmento and S ReisldquoSolid lipid nanoparticles a potential multifunctional approachtowards rheumatoid arthritis theranosticsrdquo Molecules vol 20no 6 pp 11103ndash11118 2015

[52] A Seyfoddin and R Al-Kassas ldquoDevelopment of solid lipidnanoparticles and nanostructured lipid carriers for improvingocular delivery of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 4 pp 508ndash519 2013

[53] A Seyfoddin T Sherwin D V Patel et al ldquoEx vivo and in vivoevaluation of chitosan coated nanostructured lipid carriers forocular delivery of acyclovirrdquo Current Drug Delivery In press

Submit your manuscripts athttpwwwhindawicom

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CorrosionInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Polymer ScienceInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CeramicsJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CompositesJournal of

NanoparticlesJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Biomaterials

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

NanoscienceJournal of

TextilesHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Journal of

NanotechnologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

CrystallographyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CoatingsJournal of

Advances in

Materials Science and EngineeringHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Smart Materials Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MetallurgyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

MaterialsJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Nano

materials

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal ofNanomaterials

Journal of Nanomaterials 7

bioavailability of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 11 pp 1809ndash1817 2013

[19] B B Ghera F Perret Y Chevalier and H Parrot-LopezldquoNovel nanoparticles made from amphiphilic perfluoroalkyl120572-cyclodextrin derivatives preparation characterization andapplication to the transport of acyclovirrdquo International Journalof Pharmaceutics vol 375 no 1-2 pp 155ndash162 2009

[20] U Sili A Kaya A Mert et al ldquoHerpes simplex virus encephali-tis clinical manifestations diagnosis and outcome in 106 adultpatientsrdquo Journal of Clinical Virology vol 60 no 2 pp 112ndash1182014

[21] X Zhang Y Li H Zhou et al ldquoPlasma metabolic profilinganalysis of nephrotoxicity induced by acyclovir using metabo-nomics coupled with multivariate data analysisrdquo Journal ofPharmaceutical and Biomedical Analysis C vol 97 pp 151ndash1562014

[22] A Seedat and G Winnett ldquoAcyclovir-induced acute renalfailure and the importance of an expanding waist linerdquo BMJCase Reports 2012

[23] H Lu Y-J Han J-D Xu W-M Xing and J Chen ldquoPro-teomic characterization of acyclovir-induced nephrotoxicity ina mouse modelrdquo PLoS ONE vol 9 no 7 Article ID e1031852014

[24] R Fleischer and M Johnson ldquoAcyclovir nephrotoxicity a casereport highlighting the importance of prevention detectionand treatment of acyclovir-induced nephropathyrdquo Case Reportsin Medicine vol 2010 Article ID 602783 3 pages 2010

[25] A O Kamel G A S Awad A S Geneidi and N D MortadaldquoPreparation of intravenous stealthy acyclovir nanoparticleswith increased mean residence timerdquo AAPS PharmSciTech vol10 no 4 pp 1427ndash1436 2009

[26] S Gupta A Agarwal N K Gupta G Saraogi H Agrawal andG P Agrawal ldquoGalactose decorated PLGA nanoparticles forhepatic delivery of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 12 pp 1866ndash1873 2013

[27] Y Jin L Tong P Ai M Li and X Hou ldquoSelf-assembled drugdelivery systems 1 Properties and in vitroin vivo behaviorof acyclovir self-assembled nanoparticles (SAN)rdquo InternationalJournal of Pharmaceutics vol 309 no 1-2 pp 199ndash207 2006

[28] S Rao M J Abzug P Carosone-Link et al ldquoIntravenousacyclovir and renal dysfunction in children A Matched CaseControl Studyrdquo The Journal of Pediatrics vol 166 no 6 pp1462e4ndash1468e4 2015

[29] A B Nair ldquoQuantification of uptake and clearance of acyclovirin skin layersrdquo Antiviral Therapy vol 21 no 1 pp 17ndash25 2015

[30] S Ghosh V Jhanji E Lamoureux H R Taylor and R BVajpayee ldquoAcyclovir therapy in prevention of recurrent herpetickeratitis following penetrating keratoplastyrdquo American Journalof Ophthalmology vol 145 no 2 pp 198ndash202 2008

[31] G E Parry P Dunn V P Shah and L K Pershing ldquoAcyclovirbioavailability in human skinrdquo The Journal of InvestigativeDermatology vol 98 no 6 pp 856ndash863 1992

[32] S A Qureshi M Jiang K K Midha and J P Skelly ldquoInvitro evaluation of percutaneous absorption of an acyclovirproduct using intact and tape-stripped human skinrdquo Journal ofPharmacy amp Pharmaceutical Sciences vol 1 no 3 pp 102ndash1071998

[33] J C Schwarz V Klang S Karall D Mahrhauser G P Reschand C Valenta ldquoOptimisation of multiple WOW nanoemul-sions for dermal delivery of aciclovirrdquo International Journal ofPharmaceutics vol 435 no 1 pp 69ndash75 2012

[34] G Shishu S Rajan and Kamalpreet ldquoDevelopment of novelmicroemulsion-based topical formulations of acyclovir for thetreatment of cutaneous herpetic infectionsrdquo AAPS Pharm-SciTech vol 10 no 2 pp 559ndash565 2009

[35] R Cortesi L Ravani E Menegatti M Drechsler and EEsposito ldquoColloidal dispersions for the delivery of acyclovir AComparative Studyrdquo Indian Journal of Pharmaceutical Sciencesvol 73 no 6 pp 687ndash693 2011

[36] D Ramyadevi and P Sandhya ldquoDual sustained release deliverysystem for multiple route therapy of an antiviral drugrdquo DrugDelivery vol 21 no 4 pp 276ndash292 2014

[37] E Miserocchi G Fogliato I Bianchi F Bandello and GModorati ldquoClinical features of ocular herpetic infection in anItalian referral centerrdquo Cornea vol 33 no 6 pp 565ndash570 2014

[38] S Burrel D Boutolleau G Azar et al ldquoPhenotypic andgenotypic characterization of acyclovir-resistant corneal HSV-1 isolates from immunocompetent patients with recurrentherpetic keratitisrdquo Journal of Clinical Virology vol 58 no 1 pp321ndash324 2013

[39] O Alekseev A H Tran and J Azizkhan-Clifford ldquoEx vivoorganotypic corneal model of acute epithelial herpes simplexvirus type I infectionrdquo Journal of Visualized Experiments no 69Article ID e3631 2012

[40] C Bucolo F Drago and S Salomone ldquoOcular drug deliverya clue from nanotechnologyrdquo Frontiers in Pharmacology vol 3article 188 2012

[41] D D Garcia Q Farjo D C Musch and A Sugar ldquoEffect ofprophylactic oral acyclovir after penetrating keratoplasty forherpes simplex keratitisrdquo Cornea vol 26 no 8 pp 930ndash9342007

[42] M Fresta A M Panico C Bucolo C Giannavola and GPuglisi ldquoCharacterization and in-vivo ocular absorption ofliposome-encapsulated acyclovirrdquoThe Journal of Pharmacy andPharmacology vol 51 no 5 pp 565ndash576 1999

[43] S L Law K J Huang and C H Chiang ldquoAcyclovir-containingliposomes for potential ocular delivery corneal penetration andabsorptionrdquo Journal of Controlled Release vol 63 no 1-2 pp135ndash140 2000

[44] P Chetoni S Rossi S Burgalassi D Monti S Mariotti and MF Saettone ldquoComparison of liposome-encapsulated acyclovirwith acyclovir ointment ocular pharmacokinetics in rabbitsrdquoJournal of Ocular Pharmacology andTherapeutics vol 20 no 2pp 169ndash177 2004

[45] C Giannavola C Bucolo A Maltese et al ldquoInfluence ofpreparation conditions on acyclovir-loaded poly-dl-lactic acidnanospheres and effect of PEG coating on ocular drug bioavail-abilityrdquo Pharmaceutical Research vol 20 no 4 pp 584ndash5902003

[46] M Fresta G Fontana C Bucolo G Cavallaro G Giammonaand G Puglisi ldquoOcular tolerability and in vivo bioavailability ofpoly(ethylene glycol) (PEG)-coated polyethyl-2-cyanoacrylatenanosphere-encapsulated acyclovirrdquo Journal of PharmaceuticalSciences vol 90 no 3 pp 288ndash297 2001

[47] A Leonardi C Bucolo G L Romano et al ldquoInfluence ofdifferent surfactants on the technological properties and in vivoocular tolerability of lipid nanoparticlesrdquo International Journalof Pharmaceutics vol 470 no 1-2 pp 133ndash140 2014

[48] R Pignatello C Bucolo and G Puglisi ldquoOcular tolerability ofEudragit RS100 and RL100 nanosuspensions as carriers forophthalmic controlled drug deliveryrdquo Journal of PharmaceuticalSciences vol 91 no 12 pp 2636ndash2641 2002

8 Journal of Nanomaterials

[49] C Bucolo A Maltese F Maugeri B Busa G Puglisi and RPignatello ldquoEudragit RL100 nanoparticle system for the oph-thalmic delivery of cloricromenerdquoThe Journal of Pharmacy andPharmacology vol 56 no 7 pp 841ndash846 2004

[50] S Misra K Chopra V R Sinha and B Medhi ldquoGalantamine-loaded solidndashlipid nanoparticles for enhanced brain deliverypreparation characterization in vitro and in vivo evaluationsrdquoDrug Delivery vol 23 no 4 pp 1434ndash1443 2016

[51] J Albuquerque C C Moura B Sarmento and S ReisldquoSolid lipid nanoparticles a potential multifunctional approachtowards rheumatoid arthritis theranosticsrdquo Molecules vol 20no 6 pp 11103ndash11118 2015

[52] A Seyfoddin and R Al-Kassas ldquoDevelopment of solid lipidnanoparticles and nanostructured lipid carriers for improvingocular delivery of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 4 pp 508ndash519 2013

[53] A Seyfoddin T Sherwin D V Patel et al ldquoEx vivo and in vivoevaluation of chitosan coated nanostructured lipid carriers forocular delivery of acyclovirrdquo Current Drug Delivery In press

Submit your manuscripts athttpwwwhindawicom

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CorrosionInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Polymer ScienceInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CeramicsJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CompositesJournal of

NanoparticlesJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Biomaterials

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

NanoscienceJournal of

TextilesHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Journal of

NanotechnologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

CrystallographyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CoatingsJournal of

Advances in

Materials Science and EngineeringHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Smart Materials Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MetallurgyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

MaterialsJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Nano

materials

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal ofNanomaterials

8 Journal of Nanomaterials

[49] C Bucolo A Maltese F Maugeri B Busa G Puglisi and RPignatello ldquoEudragit RL100 nanoparticle system for the oph-thalmic delivery of cloricromenerdquoThe Journal of Pharmacy andPharmacology vol 56 no 7 pp 841ndash846 2004

[50] S Misra K Chopra V R Sinha and B Medhi ldquoGalantamine-loaded solidndashlipid nanoparticles for enhanced brain deliverypreparation characterization in vitro and in vivo evaluationsrdquoDrug Delivery vol 23 no 4 pp 1434ndash1443 2016

[51] J Albuquerque C C Moura B Sarmento and S ReisldquoSolid lipid nanoparticles a potential multifunctional approachtowards rheumatoid arthritis theranosticsrdquo Molecules vol 20no 6 pp 11103ndash11118 2015

[52] A Seyfoddin and R Al-Kassas ldquoDevelopment of solid lipidnanoparticles and nanostructured lipid carriers for improvingocular delivery of acyclovirrdquo Drug Development and IndustrialPharmacy vol 39 no 4 pp 508ndash519 2013

[53] A Seyfoddin T Sherwin D V Patel et al ldquoEx vivo and in vivoevaluation of chitosan coated nanostructured lipid carriers forocular delivery of acyclovirrdquo Current Drug Delivery In press

Submit your manuscripts athttpwwwhindawicom

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CorrosionInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Polymer ScienceInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CeramicsJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CompositesJournal of

NanoparticlesJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Biomaterials

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

NanoscienceJournal of

TextilesHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Journal of

NanotechnologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

CrystallographyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CoatingsJournal of

Advances in

Materials Science and EngineeringHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Smart Materials Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MetallurgyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

MaterialsJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Nano

materials

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal ofNanomaterials

Submit your manuscripts athttpwwwhindawicom

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CorrosionInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Polymer ScienceInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CeramicsJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CompositesJournal of

NanoparticlesJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Biomaterials

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

NanoscienceJournal of

TextilesHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Journal of

NanotechnologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

CrystallographyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CoatingsJournal of

Advances in

Materials Science and EngineeringHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Smart Materials Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MetallurgyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

MaterialsJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Nano

materials

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal ofNanomaterials