evaluation between the usability and physicochemical...

Research ArticleEvaluation between the Usability and Physicochemical Propertyof Acyclovir Ointments

Yutaka Inoue Akiho Mitsumori Itsuka Shinohara Sachie NarumiIsamuMurata and Ikuo Kanamoto

Laboratory of Drug Safety Management Faculty of Pharmacy and Pharmaceutical Sciences Josai University 1-1 KeyakidaiSakado-shi Saitama 3500295 Japan

Correspondence should be addressed to Yutaka Inoue yinouejosaiacjp

Received 5 April 2018 Accepted 15 July 2018 Published 1 August 2018

Academic Editor Tetsuya Ozeki

Copyright copy 2018 Yutaka Inoue et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

A lot of prescription medicines have become switch over-the-counter (OTC) medicines However additives in brand-name drugsgeneric drugs and switch OTC drugs differ therefore the feelings associated with the use of these medicines vary for patientsTheaim of this study was to compare the physicochemical properties and the feeling of use (assuming skin as an index of usability) ofacyclovir (ACV) ointments Five ACV ointments were used ACV-A a brand-name drug ACV-B and ACV-C generic drugs andACV-D and ACV-E switch OTC drugs The physicochemical properties were evaluated by determining the content uniformitywater content flattening viscosity and viscoelasticity and near-infrared (NIR) absorption spectroscopy Skin frictionwasmeasuredto evaluate the feeling associated with use Results of the content uniformity test indicated that the ACV content was uniform andequivalence was observed Measurement of moisture content indicated that this parameter differed in each ointment preparationThe yield value which was calculated by measuring flattening was 44167 dynecm2 for ACV-A 11757 dynecm2 for ACV-B 21149dynecm2 for ACV-C 42345 dynecm2 for ACV-D and 36207 dynecm2 for ACV-E Measurement of viscosity and viscoelasticityrevealed that viscosity increased with time and the viscoelasticity of each ointment The second derivative of the NIR spectrumrevealed that ACV-B and ACV-C had a wider spectrum of absorption than the other ointments ACV-B had lesser friction thanother ointments These findings suggest that differences in the type and content of additives (macrogol) result in differences in thephysicochemical properties of individual ointments

1 Introduction

A lot of prescription medicines become switch OTC drugsmaking it possible to purchase these medicines withoutprescription with instructions from a pharmacist for self-medication [1 2] Famotidine a gastric acid secretioninhibitor and indomethacin an anti-inflammatory drug areswitch OTC drugs for internal medicine and terbinafinehydrochloride an antifungal drug and vidarabine an antivi-ral drug are switch OTC drugs for external medicine Thesemedicines require pharmacotherapy for patient care througha counter service or a recommendation from a pharmacistto receive a medical examination [3] Generic drugs can alsobe prescription drugs and are prescribed as needed by thepatient [4] However the additives contained in brand-namedrugs generic drugs and switch OTC drugs differ thereforepatient experience of these drugs varies

For example physicochemical properties of vidarabinewere evaluated using brand-name drugs generic drugs andswitch OTC drugs and differences in the viscosity of eachformulation due to differences in additives in the formulationwere reported [5] Thus the additives in brand-name drugsgeneric drugs and switch OTC drugs differ and the feelingsassociatedwith the use of different drug formulationsmust beconsidered Thus pharmacists can advise on self-medicationby providing instructions to patients through an understand-ing of the physicochemical properties of each formulationHowever currently a few reports have compared the physico-chemical characteristics of brand-name drugs generic drugsand switch OTC drugs

Acyclovir (ACV) is a commonly used guanine analogantiviral drug It assumes its active form when phosphory-lated in infected cells and subsequently prevents viral growth[6 7] ACV is used for the prevention and treatment of

HindawiJournal of PharmaceuticsVolume 2018 Article ID 8761394 8 pageshttpsdoiorg10115520188761394

2 Journal of Pharmaceutics

Table 1 Additive of ACV ointment each formulation

Brand name Lot number Serial number AdditiveZovirax Ointment 5 3E7F ACV-A Macrogol 300 macrogol 1500Acyclovir Ointment 5 ldquoTEVArdquo CAO11 ACV-B Macrogol 300 macrogol 400 macrogol 4000Acyclovir Ointment 5 ldquoTOWArdquo A125 ACV-C Macrogol 400 macrogol 4000 pH adjusterActivir UW3M ACV-D MacrogolHifuru AC Y503 ACV-E Macrogol

herpes simplex virus I (cold sores) and herpes simplex virusII (genital herpes) infections ACV is used as an internalmedicine ointment and cream Also these ACV formula-tions are available as both brand-name and generic drugsDifferences in the viscosity and viscoelasticity of brand-nameand generic ACV creams have been previously reported[8] Recently switch OTC drugs for ACV ointments whichrequire pharmacist guidance have been used

Previously these ACV creams have reported on theviscosity and incompatibility of original drugs and genericproducts [8] However in this study ACV ointment wasused to evaluate physical properties of OTC drugs as wellas prescription drugs (original drugs and generic products)In order to predict an indication of usability in clinicalperforming the evaluation due to friction meter is believedto play a role in providing information to healthcare pro-fessionals and patients In this study the physicochemicalproperties of ACV formulations were examined ZoviraxOintment 5 a brand-name drug Acyclovir Ointment5 ldquoTEVArdquo Aciclovir Ointment 5 ldquoTOWArdquo a genericdrug and Activir and Hifuru AC switch OTC drugsThe major additive contained in the brand-name genericand switch OTC ACV ointments is macrogol It has beenreported that the viscosity of polyethylene glycol a macrogolvaries depending on the average molecular weight and thatdifferences in the feelings associated with the use of thepreparation vary when polyethylene glycol is used as anadditive [9] Therefore differences in the average molecularweight of macrogol were assessed and the viscosity andviscoelasticity of each ointment were evaluated Additionallythe skin friction of each ointment was measured and thefeeling of use on the skin was evaluated Furthermore toinvestigate the molecular behavior of the additive in eachformulation the near-infrared (NIR) absorption spectrumwas measured It would be considered to become an itemin visualization information of each ointment difference somapping by main analysis statistical analysis was evaluated

2 Materials and Methods

21 Materials Commercial formulations of ACV ointmentswere purchased The brand-name ointment was ZoviraxOintment 5 (GlaxoSmithKlineCo Ltd) generic ointmentswere Acyclovir Ointment 5 ldquoTEVArdquo (Teva Takeda PharmaLtd) and Acyclovir Ointment 5 ldquoTOWArdquo (Towa Phar-maceutical Co Ltd) and OTC ointments were Activir(GlaxoSmithKline ConsumerHealthcare JapanCo Ltd) andHifuruAC (BankyoPharmaceutical Co Ltd)Thepropertiesand additives of each formulation are shown in Table 1

ACV crystal was purchased from Tokyo Kasei Co LtdOther reagents were of special commercial grade (Wako PureChemical Industries Co Ltd)

22 Methods

221 Content Uniformity Test For the assay approximately100 mg of each ointment was weighed 125 mL of dilutedsodium hydroxide solution and 375 mL of distilled waterwere added and dissolved Then 01 molL hydrochloric acidsolution was added to 75 mL of each ointment solution tomake 100 mL and test solutions were prepared Approxi-mately 10mg of ACVwas weighed diluted sodiumhydroxidesolution was then added to reach 10 mL Then 75 mL ofdiluted sodium hydroxide solution was added to the ACVsolution and distilled water was added to make 50 mLHydrochloric acid solution (01 molL) was added to reach100 mL and a standard solution was prepared Measurementswere made using a UV-vis recording spectrophotometer(Shimadzu UV-2500PC) Absorbance of test and standardsolutions was measured at a wavelength of 255 nm using 01molL hydrochloric acid as a control

The amount of each ACV ointment was calculated usingthe following equation

Amount of ACV (mg) =WS lowast ATASlowast1

2(1)

where WS is weighed amount of ACV standard productconverted into dehydrate (mg) AT is absorbance of testsolution and AS is absorbance of standard solution

222 Measurement of Water Content Water content wasmeasured using a Karl-Fisher moisture content meter (KyotoElectronics Manufacturing Co Ltd MKV-710M) KEMAQUATR-3 (Kyoto ElectronicsManufacturingCo Ltd) wasused as the titrant and KEM AQUA FAT (Kyoto ElectronicsManufacturing Co Ltd) served as the dehydrated solventThe water content in 003 g of each sample was measuredthree times at 25∘C

223 Measurement of Flattening Spreadability was mea-sured using a spread meter (Rigo) with a measuring temper-ature of 25∘C Spread diameter was measured after 5 10 60120 180 240 300 360 600 and 900 s

The yield value was calculated from the following formulausing the spread diameter after 180 s

F = 47040 lowast G lowast V1205872lowast D5 (2)

Journal of Pharmaceutics 3

Table 2 Content uniformity of ACV ointments

Formulation Uniformity (mean plusmn SD)ACV-A 1021 plusmn 20ACV-B 1008 plusmn 18ACV-C 1000 plusmn 14ACV-D 1031 plusmn 03ACV-E 1018 plusmn 08Nonsignificant (n=3)

where F is yield value (dynecm2) G is glass plate weight(1155g) V is sample size (cm3) andD is diameter (mm)whensample spreading stopped

224 Viscosity and Viscoelasticity Dynamic viscosity wasmeasured using a type-E rotational viscometer (Toki SangyoTVE-20H) The dynamic viscosity of 002 mL of each oint-ment was measured for 553 s at 25∘C using the viscometerwith a 3∘times R97 cone rotor Measurements were made ata shear rate of 001-008 997888rarr 008 -001 sminus1 (001 sminus1 60 sthe other shear rate 30 s) The viscosity was measured at ashear rate of 008 sminus1 for 276 s Viscoelasticity measured therecovery and stress at a shear rate of 1 s before the shear ratechanges The viscoelasticity of each ointment was measuredthree times under the same conditions

225 Near-Infrared Absorption Spectroscopy NIR absorp-tion spectra were recorded using a Fourier-transform near-infrared analyzer (Buchi NIRFlex N-500) Spectroscopy wasperformed at a wavelength of 1000-2500 nm and a wavenum-ber of 10000-4000 cmminus1 and spectra were recorded for 8 s at25∘C Each ointment was placed in a sample cup and the NIRabsorption spectra were measured at 1 nm intervals

226 Skin FrictionMeasurement The skin friction producedby each ointment was measured using the Frictiometer(Courage + Khazaka Electronic GmbH FR 700) A 01 gsample of each ointment was applied to artificial skin andskin friction at 25∘C was measured by agitation for 20 s at 25rpm

227 Statistical Analysis Statistical analysis was performedusing Tukeyrsquos test with plt005 considered to indicate asignificant difference

3 Results and Discussion

31 Content Uniformity Test Auniformity of content test wasconducted to assess the equivalence of ACV content in eachointment (Table 2) The percentage ACV in ACV-A ACV-BACV-C ACV-D andACV-Ewas 1021 plusmn 20 1008 plusmn 18 1000plusmn 14 1031 plusmn 0310 and 1018 plusmn 08 Tukeyrsquos test revealedno significant difference in the uniformity of content in thefive ointments Thus the contents of ACV in ACV-A ACV-B ACV-C ACV-D and ACV-E were considered uniform

32 Measurement of Moisture Content Themoisture contentof each formulation was determined The results indicated

Table 3 Spreadability of ACV ointments at 25∘C

Formulation Spreadability (mean plusmn SD)ACV-A 229 plusmn 01ACV-B 298 plusmn 02ACV-C 265 plusmn 02ACV-D 231 plusmn 03ACV-E 238 plusmn 03Value of the spreadability after 180 seconds (n=3)

that ACV-A had a moisture content of 136 plusmn 027 ACV-B had a moisture content of 322 plusmn 075 ACV-C had amoisture content of 352 plusmn 043 ACV-D had a moisturecontent of 129 plusmn 019 and ACV-E had a moisture contentof 456 plusmn 094 This indicated that the moisture content ineach formulation differed

33 Measurement of Flattening The feeling associated withthe use of a semisolid preparation can be evaluated byassessing extensibility and hardness which are indexes ofspreadability and yield value using a spread meter [10]Therefore the spreadability and yield value of each ointmentpreparation were calculated using a spread meter and thephysical properties were evaluated (Table 3 and Figures 1and 2) The spreadability was evaluated by comparing thediameters at 180 s when the spreading of each ointmentpreparation was stable The diameter of the ointment spreadin 180 s was 229 mm for ACV-A 298 mm for ACV-B265 mm for ACV-C 231 mm for ACV-D and 238 mmfor ACV-E From this the spread of ACV-B was foundto cover a wider diameter compared to that of the otherointments A similar spread of about 23 mm in diameterwas found for ACV-A ACV-D and ACV-E Next the yieldvalues of ACV-A ACV-B ACV-C ACV-D and ACV-Ewhich are indexes of hardness were calculated The yieldvalue was 44167 dynecm2 for ACV-A 11757 dynecm2 forACV-B 21149 dynecm2 for ACV-C 42345 dynecm2 forACV-D and 36207 dynecm2 for ACV-E The spreadabilityand yield value indicated that ACV ointments are soft andextensible preparations in the order of ACV-B gt ACV-C gt ACV-E gt ACV-D gt ACV-A In addition the spreaddiameters of ACV-A and ACV-D were similar and ACV-Aand ACV-D exhibited hardness and extensibility comparedwith other ointments The extensibility of ointment is dueto the additives contained in the preparation [11] Thus thedifferences in spreadability and yield value of each ointmentaffected themolecular weight andmacrogol content which isan additive contained in each ointment

34 Measurement of Viscosity and Viscoelasticity Viscositywas measured to evaluate the viscosity characteristics of eachointment (Figure 3) After 276 s ACV-A had a viscosityof 14288 Pasdots ACV-B had a viscosity of 10928 Pasdots ACV-C had a viscosity of 13231 Pasdots ACV-D had a viscosityof 14500 Pasdots and ACV-E had a viscosity of 15886 PasdotsThere was a small increase in the viscosity of ACV-B overtime compared with the other ointments Thus the ACV-B formulation undergoes little change in internal structure


y = 02 ln(x) + 219

y = 07 ln(x) + 259

y = 03 ln(x) + 249

y = 02 ln(x) + 219

y = 01 ln(x) + 230

10 100 10001Log time (s)

2122232425262728293031

Dia

met

er (m

m)

ACV-AACV-BACV-C

ACV-DACV-E

Figure 1 Average diameter of ACV ointments in Logarithm time

ACV-B ACV-C ACV-D ACV-EACV-A

lowast

lowast

lowastlowast

lowastlowast

lowastlowastlowast

lowastlowastlowastlowastlowast

0

1000

2000

3000

4000

5000

Yiel

d va

lue (

dyne

cm

2)

Figure 2 Yield value of ACV ointments at 25∘C Value of thespreadability after 180 seconds (mean plusmn SD n=3) Tukeyrsquos test wasgiven for official approval (plt005) lowast indicates that significantdifferences were seen between ACV-A and ACV-B and betweenACV-A and ACV-C (plt005 for each) lowastlowast indicates that significantdifferences were seen between ACV-B and ACV-C between ACV-B and ACV-D and between ACV-B and ACV-E (plt005 for each)lowastlowastlowast indicates that significant differences were seen betweenACV-Cand ACV-D and between ACV-C and ACV-E (plt005 for each)

when subjected to shear stress Conversely the viscosity ofACV-E changed markedly over time compared with thatof the other ointments In addition the viscosity of ACV-A ACV-C and ACV-D similarly increased with time Thediffering changes in viscosity over time between ointmentsdid not confirm the results obtained for moisture contentand spreadability As such the varying changes in viscositywith time may have been due to differences in the molecularweight and content of the additive macrogol

100 200 300 400 500 6000Time (s)

02000400060008000

1000012000140001600018000

Visc

osity

(Pamiddot

s)

ACV-AACV-BACV-C

ACV-DACV-E

Figure 3 Viscosity curves of ACV ointments at 25∘C

Up DownACV-AACV-BACV-CACV-DACV-E

005 01 015 020Shear rate (1s)

0

100

200

300

400

Shea

r stre

ss (P

a)

Figure 4 Shear stress versus shear speed curves of ACV ointments

The viscosity of each ointment preparation differedtherefore the viscoelasticity of each ointment preparationwas evaluated (Figure 4) The shear stress of ACV-B was lowwhile that of ACV-E was high compared with the other oint-ments In addition the shear stresses of ACV-A ACV-C andACV-D were similar These results indicate that ACV-B hasproperties of softness compared with the other formulationsConversely ACV-E has properties of strength compared withthe other formulations This was correlated with viscosity

The rheogram observed with an increase in shear ratediffered from that observed with a decrease in shear rate anda hysteresis loop was observed for all ointment formulationsThe presence of a hysteresis loop indicates that time is neededto recover the internal structure which changed when theshear rate increased [12] In addition it is possible to evaluatethe thixotropy that is the strength of the internal structure bythe difference in the area of the hysteresis loop of flow curves


1st run2nd run3rd run

005 01 015 020Shear rate (1s)

0

100

200

300

400Sh

ear s

tress

(Pa)

(a)


0

100

200

300

400

Shea

r stre

ss (P

a)

005 01 015 020Shear rate (1s)

(b)


0

100

200

300

400

Shea

r stre

ss (P

a)

005 01 015 020Shear rate (1s)

(c)


005 01 015 020Shear rate (1s)

0

100

200

300

400

Shea

r stre

ss (P

a)

(d)


0

100

200

300

400

Shea

r stre

ss (P

a)005 01 015 020

Shear rate (1s)

(e)

Figure 5 Viscoelasticity curves of each ACV ointment at repeated measurements (a) ACV-A (b) ACV-B (c) ACV-C (d) ACV-D and (e)ACV-E

when the shear rate is up and downThe area of the hysteresisloop of ACV-B was small and the area of the hysteresis loopof ACV-Ewas large comparedwith that of the other ointmentpreparations From the results of the viscosity measurementthe stickiness was confirmed by adding the shear stressThus from the results of viscosity and viscoelasticity ACV-B was inferred to undergo less change in its internal structurewhen subjected shear stress and to have properties of softnesscompared with the other ointments Conversely the internalstructure of ACV-E was easily changed by shear stress with aharder formulation compared with the other ointments

Next repeatedmeasurements were performed to evaluatechanges in the robustness viscosity and viscoelasticity ofeach ointment (Figure 5) When ACV-E was subjected torepeated shear stress the shear stress decreased in the thirdrun compared with the first and second runs Thus theinternal structure of ACV-E may be susceptible to disruptionwhenACV-E is subjected to repeated shear stress In additionthe shear stress of ACV-B and ACV-C underwent minimalchange even under repeated shear stress Thus ACV-B andACV-C were considered to possess viscoelasticity and theinternal structure of ACV-B and ACV-C could be main-tained even under shear stress Additionally the shear stressof ACV-A and ACV-D increased in the third run comparedto that in the first and second runs Thus when ACV-A andACV-Dwere subjected to repeated shear stress there was lessdisruption to their internal structures

The results obtained for viscosity and viscoelasticitydiffered from those obtained for spreadability and yield valueThis suggests that there are differences in the extensibilityand change in the internal structure of each ointmentThe viscosity and viscoelasticity of cream preparations havebeen reported to vary depending on the proportion of oilcontained in cream [13] Therefore in this study differencesin viscosity and viscoelasticity among the ointment prepa-rations were due to differences in moisture content and themolecular weight and content of macrogol In addition fromthe results obtained thus far ACV-A and ACV-D appear tohave similar properties Thus macrogol which is containedby ACV-A and ACV-D as an additive accounted for theirsimilar molecular weight and content

35 Near-Infrared Absorption Spectroscopy NIR absorptionspectra were recorded to verify differences in the water oroil content of each formulation (Figure 6) The absorptionspectrum of the olefin group (-CH

2) in the oleaginous base

was observed at 4300 and 5800 cmminus1 and that of the hydroxylgroup (-OH) caused by moisture was observed around 5200cmminus1The current study evaluated the oil andwater content ofeach formulation focusing on these spectra [14 15] The sec-ond derivative of the NIR absorption spectrum revealed thatACV-B and ACV-C possessed a wider absorption spectrumthan the other ointments due to the olefin group (Figure 6(a))Moreover ACV-E possessed a larger spectrum than the other


0

01

02

03

04

Refle

ctan

ce (

)

minus3

minus2

minus1

0

1

2

3

4

510052005300

2nd

diffe

rent

iatio

n

0

1

2

3

4

570058005900

2nd

diffe

rent

iatio

n

(a) (b)

Wavenumber (cmminus1)Wavenumber (cmminus1

)

40005000600070008000900010000Wavenumber (cmminus1

)

ACV-AACV-BACV-C

ACV-DACV-E

minus3

minus2

minus1

Figure 6 Near-infrared absorption spectra of ACV ointments observed to 4000-10000 cmminus1 (a) 2nd differential near-infrared absorptionspectra of ACV ointments observed to 5700-5950 cmminus1 (b) 2nd differential near-infrared absorption spectra of ACV ointments observedto 5100-5300 cmminus1

ointments due to the hydroxyl group (Figure 6(b)) Fromthese results differences in oleaginous base and moisturecontent of each formulation were clarified

To evaluate differences in the principal component ofeach formulation a principal component analysis was per-formed (Figure 7) [16] In principal component 1 (PC1) ACV-A and ACV-D were similar ACV-B and ACV-C were similarand ACV-E differed from other ointments In principalcomponent 2 (PC2) ACV-A and ACV-D were similar ACV-B and ACV-C were similar and ACV-E differed from otherointments Moisture content analysis and NIR absorptionspectroscopy suggested that PC1 reflected differences in thewater content of each formulation PC2 differed between thefive formulations PC2 was considered to reflect differencesin the molecular weight and the content of oleaginous basesand macrogol in ACV ointments These results indicate thatointment spreadability is due to the moisture content ofeach formulation and the molecular weight and contentof macrogol contained in each ointment In addition the

viscosity and viscoelasticity of ointments were due to themolecular weight and content of macrogol contained in eachointment Generally macrogol is known to have differentproperties depending on the molecular weight of macrogolFor example macrogol 400 is liquid and macrogol 4000 issolid at normal temperature and the viscosity of macro-gol 400 is lower compared with the viscosity of macrogol4000 Therefore the results of spreadability viscosity andviscoelasticity are considered due to the difference of themolecular weight of macrogol and each macrogol contentof each ointment Comparing the additives contained ineach ointment ACV-B and ACV-C contain macrogol 4000However these results indicated that ACV-B and ACV-Cwere soft and extensible preparations compared to other oint-ments Therefore the properties of ACV-B and ACV-C wereconsidered due to the difference of each macrogol contentIn addition the difference of the formulation process of eachointment was also considered to contribute to the propertiesof the ointment preparation Furthermore the molecular


minus05

minus04

minus03

minus02

minus01

0

01

02

03

04

05

PC 2

minus04 minus03 minus02 minus01 0 01 02 03 04 05minus05PC 1

ACV-AACV-BACV-C

ACV-DACV-E

Figure 7 Principal component analysis of ACV ointments

0

50

100

150

200

250

300

350

400

0 5 10 15 20

Fric

tion

(N)

Time (s)

ACV-AACV-BACV-C

ACV-DACV-E

Figure 8 Skin friction of ACV ointments respectively (n=5)

weight of macrogol in ACV-D has not been reportedHowever the moisture content spreadability viscosity andviscoelasticity of ACV-D were similar to those of ACV-Atherefore the molecular weight of macrogol contained inACV-D was presumed to be 300 and 1500 which was themolecular weight of macrogol contained in ACV-A Themolecular weight of macrogol in ACV-E as an additive hasnot been reported However from the viscosity measurementand the second derivative of NIR absorption spectra themolecular weight of macrogol with ACV-E was inferredto be lower than that with ACV-B and ACV-C Howevergenerally the viscosity of high-molecular-weight macrogol ishigher than the viscosity of low-molecular-weight macrogolTherefore the properties of ACV-E were considered due tothe difference of each macrogol content and the productionprocess of each ointment

36 Skin FrictionMeasurement TheFrictiometer was used tomeasure friction in order to evaluate the feeling of the creamswhen applied to the skin (Figure 8) This was also used toevaluate the feeling of cosmetics on the skin [17] After 15 sACV-A had a friction measurement of 3565 N ACV-B had1216 N ACV-C had 1624 N ACV-D had 3497 N and ACV-E had 1875 N The magnitude of the friction force followedthe same pattern as the yield value calculated with a spreadmeter The force of friction was inversely correlated with thespreadability and slipperiness of a semisolid preparation andwas correlated with the stickiness of the preparation ThusACV-Bwas inferred to be not sticky and to spread easilywhenapplied to human skin compared with the other ointments

4 Conclusion

A uniformity of content test revealed that ACV-A ACV-B ACV-C ACV-D and ACV-E possess equivalent ACVcontents Evaluation of the properties of each ointmentrevealed the physicochemical properties of ACV-A ACV-BACV-C ACV-D and ACV-E A skin friction test revealeddifferences in the properties of ACV-A ACV-B ACV-CACV-D and ACV-EThis study investigated the properties ofdifferent ACV formulations in a model scenario involving abrand-name ointment a generic ointment and a switch OTCointment In the future pharmacists will need to investigatethe properties of OTC formulations This will help maintainthe health of the community and encourage appropriate self-medication

Data Availability

The data described in this article are not quoted from otherstudies and are new data obtained by this research No datawere used to support this study

Disclosure

The authors alone are responsible for the content and writingof this paper

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

Acknowledgments

The authors thank Dr T Tarumi of Japan Buchi Co Ltd forhis helpful advice regarding NIR absorption measurementsThey are grateful to Dr Hiroaki Todo and Ms Mika Futakifor measuring Frictiometer

References

[1] N J Gauld F S Kelly N Kurosawa L J M Bryant L MEmmerton and S A Buetow ldquoWidening consumer access tomedicines through switching medicines to non-prescription Asix country comparisonrdquo PLoS ONE vol 9 no 9 Article ID107726 2014


[2] N Chowdhury A Haque and F Aysha ldquoInvestigation intoself-medication of drugs for primary and adjunct therapy inpsychiatric diseases among students in Chittagong City ofBangladesh A comparison between medical and nonmedicalstudentsrdquo Indian Journal of Psychological Medicine vol 34 no4 pp 313ndash317 2012

[3] K Nomura Y Kitagawa Y Yuda and H Takano-OhmuroldquoMedicine reclassification processes and regulations for properuse of over-the-counter self-care medicines in Japanrdquo RiskManagement and Healthcare Policy vol 9 pp 173ndash183 2016

[4] R Kuribayashi M Matsuhama and K Mikami ldquoRegulationof generic drugs in Japan the current situation and futureprospectsrdquoThe AAPS Journal vol 17 no 5 pp 1312ndash1316 2015

[5] Y Inoue R Shiozawa and D Niiyama ldquoCharacterization ofprescription andOTC formulations of vidarabine creamrdquoWorldJournal of Pharmaceutical Sciences vol 5 no 1 pp 11ndash18 2017

[6] R Joseph and K G Kumar ldquoElectrochemical sensing of acyclo-vir at a gold electrode modified with 2-mercaptobenzothia-zole-[5101520-tetrakis-(3-methoxy-4-hydroxyphenyl)porphy-rinato]copper(II)rdquo Analytical Sciences vol 27 no 1 pp 67ndash722011

[7] M Suzuki T Okuda and K Shiraki ldquoSynergistic antiviralactivity of acyclovir and vidarabine against herpes simplex virustypes 1 and 2 and varicella-zoster virusrdquo Antiviral Research vol72 no 2 pp 157ndash161 2006

[8] Y Inoue K Furuya M Matumoto I Murata M Kimura andI Kanamoto ldquoA comparison of the physicochemical propertiesand a sensory test of Acyclovir creamsrdquo International Journal ofPharmaceutics vol 436 no 1-2 pp 265ndash271 2012

[9] G T Pedro F Camacho and B Gabriel ldquoDensity and viscosityof concentrated aqueous solutions of polyethylene glycolrdquoJournal of Chemical amp Engineering Data vol 39 no 3 pp 611ndash614 1994

[10] Y Inoue M Matsumoto M Kimura T Tanaka and I Kan-amoto ldquoComparison of the properties of brand-name and ge-neric nadifloxacin creamsrdquoMedicina vol 47 no 11 pp 616ndash6222011

[11] S Kitagawa R Yutani R-I Kodani and R Teraoka ldquoDiffer-ences in the rheological properties and mixing compatibilitywith heparinoid cream of brand name and generic steroidalointments The effects of their surfactantsrdquo Results in PharmaSciences vol 6 pp 7ndash14 2016

[12] Y Inoue K Suzuki R Maeda A Shimura I Murata and IKanamoto ldquoEvaluation of formulation properties and skin pen-etration in the same additive-containing formulationrdquoResults inPharma Sciences vol 4 pp 42ndash49 2014

[13] E Fredrick P Walstra and K Dewettinck ldquoFactors governingpartial coalescence in oil-in-water emulsionsrdquo Advances inColloid and Interface Science vol 153 no 1-2 pp 30ndash42 2010

[14] M JMaltesen S Bjerregaard L Hovgaard S HavelundM vande Weert and H Grohganz ldquoMultivariate analysis of phenol infreeze-dried and spray-dried insulin formulations by NIR andFTIRrdquo AAPS PharmSciTech vol 12 no 2 pp 627ndash636 2011

[15] E-J Suh Y-A Woo and H-J Kim ldquoDetermination of watercontent in skin by using a FT near infrared spectrometerrdquoArchives of Pharmacal Research vol 28 no 4 pp 458ndash4622005

[16] J Luypaert S Heuerding S De Jong and D L Massart ldquoAnevaluation of direct orthogonal signal correction and other pre-processing methods for the classification of clinical study lotsof a dermatological creamrdquo Journal of Pharmaceutical and Bio-medical Analysis vol 30 no 3 pp 453ndash466 2002

[17] P Neto M Ferreira F Bahia and P Costa ldquoImprovement ofthe methods for skin mechanical properties evaluation throughcorrelation between different techniques and factor analysisrdquoSkin Research and Technology vol 19 no 4 pp 405ndash416 2013

Medicinal ChemistryInternational Journal of

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ToxicologyJournal of


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Table 1 Additive of ACV ointment each formulation

Brand name Lot number Serial number AdditiveZovirax Ointment 5 3E7F ACV-A Macrogol 300 macrogol 1500Acyclovir Ointment 5 ldquoTEVArdquo CAO11 ACV-B Macrogol 300 macrogol 400 macrogol 4000Acyclovir Ointment 5 ldquoTOWArdquo A125 ACV-C Macrogol 400 macrogol 4000 pH adjusterActivir UW3M ACV-D MacrogolHifuru AC Y503 ACV-E Macrogol

herpes simplex virus I (cold sores) and herpes simplex virusII (genital herpes) infections ACV is used as an internalmedicine ointment and cream Also these ACV formula-tions are available as both brand-name and generic drugsDifferences in the viscosity and viscoelasticity of brand-nameand generic ACV creams have been previously reported[8] Recently switch OTC drugs for ACV ointments whichrequire pharmacist guidance have been used

Previously these ACV creams have reported on theviscosity and incompatibility of original drugs and genericproducts [8] However in this study ACV ointment wasused to evaluate physical properties of OTC drugs as wellas prescription drugs (original drugs and generic products)In order to predict an indication of usability in clinicalperforming the evaluation due to friction meter is believedto play a role in providing information to healthcare pro-fessionals and patients In this study the physicochemicalproperties of ACV formulations were examined ZoviraxOintment 5 a brand-name drug Acyclovir Ointment5 ldquoTEVArdquo Aciclovir Ointment 5 ldquoTOWArdquo a genericdrug and Activir and Hifuru AC switch OTC drugsThe major additive contained in the brand-name genericand switch OTC ACV ointments is macrogol It has beenreported that the viscosity of polyethylene glycol a macrogolvaries depending on the average molecular weight and thatdifferences in the feelings associated with the use of thepreparation vary when polyethylene glycol is used as anadditive [9] Therefore differences in the average molecularweight of macrogol were assessed and the viscosity andviscoelasticity of each ointment were evaluated Additionallythe skin friction of each ointment was measured and thefeeling of use on the skin was evaluated Furthermore toinvestigate the molecular behavior of the additive in eachformulation the near-infrared (NIR) absorption spectrumwas measured It would be considered to become an itemin visualization information of each ointment difference somapping by main analysis statistical analysis was evaluated

2 Materials and Methods

21 Materials Commercial formulations of ACV ointmentswere purchased The brand-name ointment was ZoviraxOintment 5 (GlaxoSmithKlineCo Ltd) generic ointmentswere Acyclovir Ointment 5 ldquoTEVArdquo (Teva Takeda PharmaLtd) and Acyclovir Ointment 5 ldquoTOWArdquo (Towa Phar-maceutical Co Ltd) and OTC ointments were Activir(GlaxoSmithKline ConsumerHealthcare JapanCo Ltd) andHifuruAC (BankyoPharmaceutical Co Ltd)Thepropertiesand additives of each formulation are shown in Table 1

ACV crystal was purchased from Tokyo Kasei Co LtdOther reagents were of special commercial grade (Wako PureChemical Industries Co Ltd)

22 Methods

221 Content Uniformity Test For the assay approximately100 mg of each ointment was weighed 125 mL of dilutedsodium hydroxide solution and 375 mL of distilled waterwere added and dissolved Then 01 molL hydrochloric acidsolution was added to 75 mL of each ointment solution tomake 100 mL and test solutions were prepared Approxi-mately 10mg of ACVwas weighed diluted sodiumhydroxidesolution was then added to reach 10 mL Then 75 mL ofdiluted sodium hydroxide solution was added to the ACVsolution and distilled water was added to make 50 mLHydrochloric acid solution (01 molL) was added to reach100 mL and a standard solution was prepared Measurementswere made using a UV-vis recording spectrophotometer(Shimadzu UV-2500PC) Absorbance of test and standardsolutions was measured at a wavelength of 255 nm using 01molL hydrochloric acid as a control

The amount of each ACV ointment was calculated usingthe following equation

Amount of ACV (mg) =WS lowast ATASlowast1

2(1)

where WS is weighed amount of ACV standard productconverted into dehydrate (mg) AT is absorbance of testsolution and AS is absorbance of standard solution

222 Measurement of Water Content Water content wasmeasured using a Karl-Fisher moisture content meter (KyotoElectronics Manufacturing Co Ltd MKV-710M) KEMAQUATR-3 (Kyoto ElectronicsManufacturingCo Ltd) wasused as the titrant and KEM AQUA FAT (Kyoto ElectronicsManufacturing Co Ltd) served as the dehydrated solventThe water content in 003 g of each sample was measuredthree times at 25∘C

223 Measurement of Flattening Spreadability was mea-sured using a spread meter (Rigo) with a measuring temper-ature of 25∘C Spread diameter was measured after 5 10 60120 180 240 300 360 600 and 900 s

The yield value was calculated from the following formulausing the spread diameter after 180 s

F = 47040 lowast G lowast V1205872lowast D5 (2)


















y = 02 ln(x) + 219

y = 07 ln(x) + 259

y = 03 ln(x) + 249

y = 02 ln(x) + 219

y = 01 ln(x) + 230

10 100 10001Log time (s)

2122232425262728293031

Dia

met

er (m

m)

ACV-AACV-BACV-C

ACV-DACV-E



lowast

lowast

lowastlowast

lowastlowast

lowastlowastlowast


0

1000

2000

3000

4000

5000

Yiel

d va

lue (

dyne

cm

2)



100 200 300 400 500 6000Time (s)

02000400060008000

1000012000140001600018000

Visc

osity

(Pamiddot

s)

ACV-AACV-BACV-C

ACV-DACV-E



005 01 015 020Shear rate (1s)

0

100

200

300

400

Shea

r stre

ss (P

a)






005 01 015 020Shear rate (1s)

0

100

200

300

400Sh

ear s

tress

(Pa)

(a)


0

100

200

300

400

Shea

r stre

ss (P

a)

005 01 015 020Shear rate (1s)

(b)


0

100

200

300

400

Shea

r stre

ss (P

a)

005 01 015 020Shear rate (1s)

(c)


005 01 015 020Shear rate (1s)

0

100

200

300

400

Shea

r stre

ss (P

a)

(d)


0

100

200

300

400

Shea

r stre

ss (P

a)005 01 015 020

Shear rate (1s)

(e)









0

01

02

03

04

Refle

ctan

ce (

)

minus3

minus2

minus1

0

1

2

3

4

510052005300

2nd

diffe

rent

iatio

n

0

1

2

3

4

570058005900

2nd

diffe

rent

iatio

n

(a) (b)


)


)

ACV-AACV-BACV-C

ACV-DACV-E

minus3

minus2

minus1






minus05

minus04

minus03

minus02

minus01

0

01

02

03

04

05

PC 2


ACV-AACV-BACV-C

ACV-DACV-E


0

50

100

150

200

250

300

350

400

0 5 10 15 20

Fric

tion

(N)

Time (s)

ACV-AACV-BACV-C

ACV-DACV-E




4 Conclusion


Data Availability


Disclosure




Acknowledgments


References

























Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of



















y = 02 ln(x) + 219

y = 07 ln(x) + 259

y = 03 ln(x) + 249

y = 02 ln(x) + 219

y = 01 ln(x) + 230

10 100 10001Log time (s)

2122232425262728293031

Dia

met

er (m

m)

ACV-AACV-BACV-C

ACV-DACV-E



lowast

lowast

lowastlowast

lowastlowast

lowastlowastlowast


0

1000

2000

3000

4000

5000

Yiel

d va

lue (

dyne

cm

2)



100 200 300 400 500 6000Time (s)

02000400060008000

1000012000140001600018000

Visc

osity

(Pamiddot

s)

ACV-AACV-BACV-C

ACV-DACV-E



005 01 015 020Shear rate (1s)

0

100

200

300

400

Shea

r stre

ss (P

a)






005 01 015 020Shear rate (1s)

0

100

200

300

400Sh

ear s

tress

(Pa)

(a)


0

100

200

300

400

Shea

r stre

ss (P

a)

005 01 015 020Shear rate (1s)

(b)


0

100

200

300

400

Shea

r stre

ss (P

a)

005 01 015 020Shear rate (1s)

(c)


005 01 015 020Shear rate (1s)

0

100

200

300

400

Shea

r stre

ss (P

a)

(d)


0

100

200

300

400

Shea

r stre

ss (P

a)005 01 015 020

Shear rate (1s)

(e)









0

01

02

03

04

Refle

ctan

ce (

)

minus3

minus2

minus1

0

1

2

3

4

510052005300

2nd

diffe

rent

iatio

n

0

1

2

3

4

570058005900

2nd

diffe

rent

iatio

n

(a) (b)


)


)

ACV-AACV-BACV-C

ACV-DACV-E

minus3

minus2

minus1






minus05

minus04

minus03

minus02

minus01

0

01

02

03

04

05

PC 2


ACV-AACV-BACV-C

ACV-DACV-E


0

50

100

150

200

250

300

350

400

0 5 10 15 20

Fric

tion

(N)

Time (s)

ACV-AACV-BACV-C

ACV-DACV-E




4 Conclusion


Data Availability


Disclosure




Acknowledgments


References

























Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of




005 01 015 020Shear rate (1s)

0

100

200

300

400Sh

ear s

tress

(Pa)

(a)


0

100

200

300

400

Shea

r stre

ss (P

a)

005 01 015 020Shear rate (1s)

(b)


0

100

200

300

400

Shea

r stre

ss (P

a)

005 01 015 020Shear rate (1s)

(c)


005 01 015 020Shear rate (1s)

0

100

200

300

400

Shea

r stre

ss (P

a)

(d)


0

100

200

300

400

Shea

r stre

ss (P

a)005 01 015 020

Shear rate (1s)

(e)









0

01

02

03

04

Refle

ctan

ce (

)

minus3

minus2

minus1

0

1

2

3

4

510052005300

2nd

diffe

rent

iatio

n

0

1

2

3

4

570058005900

2nd

diffe

rent

iatio

n

(a) (b)


)


)

ACV-AACV-BACV-C

ACV-DACV-E

minus3

minus2

minus1






minus05

minus04

minus03

minus02

minus01

0

01

02

03

04

05

PC 2


ACV-AACV-BACV-C

ACV-DACV-E


0

50

100

150

200

250

300

350

400

0 5 10 15 20

Fric

tion

(N)

Time (s)

ACV-AACV-BACV-C

ACV-DACV-E




4 Conclusion


Data Availability


Disclosure




Acknowledgments


References

























Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of



0

01

02

03

04

Refle

ctan

ce (

)

minus3

minus2

minus1

0

1

2

3

4

510052005300

2nd

diffe

rent

iatio

n

0

1

2

3

4

570058005900

2nd

diffe

rent

iatio

n

(a) (b)


)


)

ACV-AACV-BACV-C

ACV-DACV-E

minus3

minus2

minus1






minus05

minus04

minus03

minus02

minus01

0

01

02

03

04

05

PC 2


ACV-AACV-BACV-C

ACV-DACV-E


0

50

100

150

200

250

300

350

400

0 5 10 15 20

Fric

tion

(N)

Time (s)

ACV-AACV-BACV-C

ACV-DACV-E




4 Conclusion


Data Availability


Disclosure




Acknowledgments


References

























Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of



minus05

minus04

minus03

minus02

minus01

0

01

02

03

04

05

PC 2


ACV-AACV-BACV-C

ACV-DACV-E


0

50

100

150

200

250

300

350

400

0 5 10 15 20

Fric

tion

(N)

Time (s)

ACV-AACV-BACV-C

ACV-DACV-E




4 Conclusion


Data Availability


Disclosure




Acknowledgments


References

























Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of

























Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of


evaluation between the usability and physicochemical...

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