c o m / l o c a t e / i j p h a r m Phuong Ha-Lien Trana,1, Thao Truong-Dinh Trana,∗, Zong Zhu Piaob,1, Toi Van Voa, Q1 Jun Bom Parkb, Jisung Limc, Kyung Teak Ohd, Yun-Seok Rheee, Beom-J
Trang 1International Journal of Pharmaceutics xxx (2013) xxx– xxx
ContentslistsavailableatSciVerseScienceDirect
jou rn a l h om ep a g e :w w w e l s e v i e r c o m / l o c a t e / i j p h a r m
Phuong Ha-Lien Trana,1, Thao Truong-Dinh Trana,∗, Zong Zhu Piaob,1, Toi Van Voa,
Q1
Jun Bom Parkb, Jisung Limc, Kyung Teak Ohd, Yun-Seok Rheee, Beom-Jin Leeb,∗
a International University, Vietnam National University, Ho Chi Minh City, Viet Nam
b College of Pharmacy, Ajou University, Suwon 443-749, Republic of Korea
c College of Pharmacy, Kangwon National University, Chuncheon 200-701, Republic of Korea
d College of Pharmacy, Chung-Ang University, Seoul 155-756, Republic of Korea
e College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea
Article history:
Received 11 November 2012
Received in revised form 24 February 2013
Accepted 8 April 2013
Available online xxx
Keywords:
Self-emulsifying solid dispersion
Enhanced dissolution
Controlled release tablet
Physicochemical properties
In vivo bioavailability
Poorlywater-solubledrugwithashorthalf-lifesuchasisradipine(IDP)offerchallengesinthecontrolled releaseformulationbecauseoflowdissolutionrateandpoorbioavailability.Self-emulsifyingsolid dis-persions(SESD)ofIDPconsistedofsurfactantandfattyacidinpoloxamer407(POX407)asacarrierand weremanufacturedbythemeltingmethod.Then,controlledreleaseHPMCmatrixtabletcontainingSESD werepreparedviadirectcompression.Thedissolutionbehaviorsandinvivobioavailabilityofcontrolled releasematrixtabletinhealthyhumanvolunteerswereinvestigated.Thephysicalpropertiesofsolid dispersionwerealsoexaminedusingdifferentialscanningcalorimetry(DSC),powderX-raydiffraction (PXRD)andscanningelectronmicroscopy(SEM).ItwasshownthatstructureofIDPwasamorphousin thesoliddispersion.ThedissolutionrateofIDPfromSESDwasmarkedlyenhancedbecauseofincreased solubilityandwettingeffect.ControlledreleaseHPMCmatrixtabletscontainingSESDreleaseddrugin
acontrolledmannerandwerestableduringstorageover3monthsat40◦C/75%RH.Furthermore,the tabletcontaining5mgIDPSESDshowedsignificantlyincreasedoralbioavailabilityandextendedplasma concentrationcomparedwiththemarketed5mgDynacirc®capsule.Acombinedmethodofsolid disper-sionandcontrolledreleasetechnologycouldprovideversatiledosageformulationscontainingIDPwith poorwatersolubilityandshorthalf-life
© 2013 Published by Elsevier B.V
1 Introduction
Solubilizationofpoorlywater-solubledrugsisveryimportant
toovercomerate-limiting dissolution,slow absorptionand low
bioavailabilityofthisdrugtype.Varioussolubilizationstrategies
therefore,havebeendevelopedsuchascomplexation,cosolvents,
micelles,microemulsions,self-microemulsifyingdrugdelivery
sys-tems or self-nanoemulsifying drug delivery systems, or solid
dispersion(SD)techniques(WongandYuen,2001;Pouton,2006;
Tranetal.,2009).SDamongthosestrategieshasbeenconsideredas
oneofcommonmethodstoenhancesolubility,dissolutionrateand
bioavailabilityofvariouspoorlywater-solubledrugs(Vasconcelos
Q2
etal.,2007;Tranetal.,2011a)
∗ Corresponding authors Tel.: +82 31 219 3442; fax: +82 31 212 3653.
E-mail addresses: ttdthao@hcmiu.edu.vn (T.T.-D Tran), beomjinlee@gmail.com
(B.-J Lee).
1 Equally contributed.
However,therearemanydifficultiesassociatedwiththe prepa-rationofSDdosageformsasfollows:theuseofunwantedorganic solvent related to the environment in the solvent evaporation method,or theproblem ofdrug stability related withelevated temperatures, and the soft and tacky physical state of the SD product to be hardly pulverized, leading to the use of more pharmaceutical excipients as well as complicated manufactur-ing procedures to compensate the poor flowing characteristics (Serajuddin,1999)
Self-emulsifyingdrugdeliverysystems,especiallyinthesolid stateobtainedbytheadditionofsomefree-flowingadsorbentsas oneofpreferablemethods,areincurrenttrendstobeinvestigated duetotheiradvantagesovertheliquidformulationforimproving thebioavailabilityofhydrophobicdrugsandgood manufacturabil-ity(Serajuddin,1999;Tangetal.,2008).Itwasrecentlyreported thataSDutilizingaself-emulsifyingcarrierlikeGelucire44/14as exposedtoaqueousmediacouldreadilymodifydrugcrystallinity andhence,improvedrugdissolutionrateofpoorlywater-soluble drug,aceclofenac(Tranetal.,2009)
0378-5173/$ – see front matter © 2013 Published by Elsevier B.V.
http://dx.doi.org/10.1016/j.ijpharm.2013.04.022
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Table 1
Formulation compositions (weight basis) of SDs containing IDP (unit: mg).
Code Drug PEG 6000 PVP K30 GUC 50/13 POX 407 Brij 98 OA Triacetin Aerosil 200 BHT
a w/w percent value based on OA.
Werecentlypublishedthatcontrolledreleasedosageforms
con-tainingself-emulsifyingornonself-emulsifyingSDsofmanypoorly
water-solubledrugswithshorteliminationhalf-lifehavebeen
con-sidered aseffective drugdeliverysystems for the treatmentof
diseasesover a longerperiod oftime (Tranetal., 2010,2011a,
2011b).AdvancedcontrolledreleaseofSDscanbeachievedbya
pertinentcombinationofpharmaceuticalpolymers(Wangetal.,
1993).Mostofall,HPMC-basedhydrophilicmatrixtabletsoffer
severaladvantagesinthedevelopmentoforalsustained-release
formulationssuchasflexibilityofreleasemodulation,simplicity
ofpreparation,lowproductioncostsandeasetoscalability(Cao
etal.,2005).Thereleasebehaviorofbothwater-solubleand
water-insolubledrugsisvariablewiththenatureoftheHPMCmatrices
asaconsequenceofthedrug–polymerinteractionviaswelling,
dif-fusionanderosionprocesses(Colomboetal.,1995;Velascoetal.,
1999)
Inthisstudy,isradipine(IDP),acalciumantagonistfortreating
hypertensionwaschosenasamodeldrug(ChrysantandCohen,
1997).IDPisknowntobepoorlywater-solubleinaqueous
solu-tion(lessthan10g/mL)(Vergeretal.,1998).Moreover,IDPis
alsoagoodcandidateforcontrolledreleasedosageformdueto
theshorteliminationhalf-life(Hafizullahetal.,2000).SESDofIDP
waspreparedusingmeltingmethodandthenloadedinto
HPMC-basedhydrophilicmatrixtabletforcontrolledreleaseofIDP.Here,
poloxamer407(POX407),atri-block copolymerconsistingof a
centralhydrophobicblockofpolypropyleneglycolflankedbythe
twohydrophilicblocksofpolyethyleneglycol,wasusedasa
car-riertoprepareSESDduetoitslowmeltingpoint,goodphysical
propertiesoffacilitatingthesolubilizationofmanypoorly
water-soluble drugs as well as its stabilization (Shin and Cho, 1997;
Chutimaworapanetal.,2000).Thesurfacemorphologyand
crys-talstructure of SESD were characterizedusing DSC, PXRD and
SEM.Thereafter,releasecharacteristicsofdrugfromSESDsandthe
HPMCmatrixtabletswerethenevaluatedinenzyme-free
simu-latedintestinalfluid(pH6.8).ThestabilityofHPMCmatrixtablets
containingSESDwasalsoinvestigatedundervariousstorage
con-ditions.Finally,thecontrolledreleasedHPMCmatrixtablet and
thecommerciallyavailableDynacirc®capsuleasareferencewere
comparedforinvivobioavailabilitystudies
2 Materials and methods
2.1 Materials
IDPasapowderformwasobtainedfromDaewoong
Pharmaceu-ticalCorp.(Seoul,Korea).Oleicacid(OA),Brij-98,microcrystalline
cellulose (Avicel® PH102), hydroxypropylmethylcellulose 4000
(HPMC-4000),polyvinylpyrrolidone(PVPK30,Kollidon®30)and
poloxamer407(POX407)wereobtainedfromSeoul
Pharmaceuti-calCorp.(Seoul,Korea).Aerosil®200waspurchasedfromEvonik
(Seoul,Korea).Butylatedhydroxyltoluene(BHT)waspurchased from Sigma (Germany) Dynacirc®CR 5mg capsule (Daewoong Pharma,Korea)waschosenasareferenceIDPformulation.Allother reagentswereofreagentgradeandusedwithoutfurther purifica-tion
2.2 Method 2.2.1 Solubilitystudy ThesolubilityofIDPwasdeterminedinvarioussolvents, surfac-tants,co-surfactantsandoils.AnexcessamountofIDPwasaddedto 1.5mLsnap-capEppendorftube(Hamburg,Germany)containing variousadditives.Theresultingmixturewassufficientlymixedand thenplacedinaconstanttemperaturewaterbathat37◦Cfor3days Aliquotswerecentrifugedat13,000rpmfor10min(Hanil,Korea) Thesupernatantlayerwascarefullycollectedandthenadjusted withaproperdilution.TheconcentrationofIDPwasanalyzedbya HPLCsystemasdescribedbelow
2.2.2 PreparationofSESDs SESDsof IDPusing various carriers wereprepared by melt-ingmethod.ThedetailedformulationcompositionsofSESDsare showninTable1(Code:SD1-SD11).IDP,surfactantandfattyacid were homogenously mixed together based on the formulation compositions.Theresultingmixtureswereslightlyheatedat var-ioustemperaturesandsufficientlystirred.Thereafter,themelted solutionwasaddedtoadsorbent(Aerosil®200).Aftersufficiently mixing,themixtureswerecooledat−38◦Cwithin2h.The solid-ifiedmasswaspulverizedthoroughlybyapestleandmortarand finally,passedthrougha50meshsievetoobtainSESDpowders
2.2.3 PreparationofcontrolledreleasedtabletcontainingSESD TheHPMC-basedmatrixtablets(150mg)werepreparedbythe directcompressionmethod.Table2showscompositionsofthe con-trolledreleaseHPMCmatrixtablets.TheSESD,HPMCpolymerand theotherexcipientsweremixedthoroughlywithapestleand mor-tar.Theresultingmixturesweredirectlycompressedintotablet usingaconventionaltabletmachineequippedwithroundpunches (8mmdiameter)andadie.Thetablethardnesswasintriplicate
Table 2
Formulation compositions (weight basis) for the preparation of HPMC-based con-trolled release matrix tablets containing SESD (unit: mg).
No SESD HPMC 4000 Avicel ® PH-102 Total weight
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measuredusingahardnesstester(ModelSVM-12,ErwekaGmbH,
Heusenstamm,Germany)
2.2.4 HPLCanalysisofIDP
A reverse phase HPLC system was used for the analysis of
IDP.TheHPLCsystem(Jasco,Tokyo,Japan)consistedofthepump
(PU-980),theUV–visiblespectrophotometricdetector(UV-975),
the autosampler (Jasco, AS-950-10), the degasser (DG-980-50),
thereverse phase column(Luna 5m C18 100A,150×4.6mm)
andintegrator(Borwin1.20 software).TheconcentrationofIDP
wasdeterminedatwavelengthofUV325nm.Themobilephase
consistedofamixtureofmethanol,deionizedwaterand
acetoni-trile(7:3:5,v/vratio)wasdegassedundervacuumfor5min.The
flowrateofthemobilephasewas1mL/min.A20lofthesample
wasinjectedintotheHPLCsystem.Thestocksolutionwas
pre-paredbydissolvingIDPinHPLC-gradeethanol(1mg/10mL)and
thenfurtherdilutedwiththemobilephase topreparestandard
solutions
2.2.5 Invitrodissolutionstudy
Invitro dissolution test of theSESDand tablet formulations
equivalentto5mgIDPwasperformedaccordingtotheUSP
dis-solution II paddle method with a rotation speed of 50rpm in
900mLoftheenzyme-freesimulatedintestinalfluid(pH6.8±0.1)
at37±0.5◦Cusingadissolutiontester(DCM1,Anyang,Korea)
Dis-solutionsampleswerecollectedat5,15,30,60,90and120min
and 1, 2, 3, 4, 6, 8, 10, 12, 16, 20 and 24h, respectively, with
replacementofequalvolumeoftemperature-equilibratedmedia
Thesinkerwasusedfordissolutionofthetablets.Thesampleswere
instantlycentrifugedat10,000rpmfor10min.Thesupernatantof
thecentrifugedsample wasdilutedwiththemobilephase.The
concentrationofsampleswasdeterminedbytheHPLCsystemas
describedpreviously
2.2.6 Thermalanalysis(DSC)
Thethermalbehaviorsofpuredrug,POXanddifferentSESD
formulationswereinvestigatedusingDupontDSC(Dupont,USA)
About3mgofsamplewasweighedinastandardopenaluminum
pan;whereasanemptypanofsametypewasusedasreference
Thesampleswereheatedfrom20to200◦C ata heatingrateof
10◦C/minunderpurgeddrynitrogen.Calibrationoftemperature
andheatflowwasperformedwithindium
2.2.7 PowderX-raydiffraction(PXRD)
PowderX-raydiffractionpatternswereobtainedforthesamples
ofpuredrug,POXanddifferentSESDformulationsusingaD5005
(Bruker,Germany)withCu-Kradiationat40kV50mA.Thesamples
werescannedinstepsof0.02◦from3◦to40◦ witharateofone
secondperstep,usingazerobackgroundsampleholder
2.2.8 Scanningelectronmicroscope(SEM)
Scanningelectronmicroscopywasusedtocharacterizethe
sur-facemorphologyandparticleshapeofthesamples.Thesamples
wereexaminedusingaJSM-5410(Jeol,Japan),atanacceleration
voltageof15kV.Thesampleswerecoatedwithathinlayerofgold
for10min
2.2.9 Stabilitystudy
TheHPMCmatrixtabletsbearingSESDwerestoredfor3months
inaplasticbottlewithsilicagelat40◦C/75%RH(relativehumidity)
Thehardnessanddissolutionprofilesforinitialandstoredsamples
weretestedatthegivenperiodoftime
2.3 Invivocomparativebioavailabilityinhealthyhuman volunteers
2.3.1 Studydesign Eight healthy human volunteers aged 20–30 years old and weighingfrom60 to70kgwereparticipated inthis studyafter submitting a written informed consent Document review and approvalfromaformallyconstitutedInstitutionalReviewBoard
inKangwonNationalUniversitywerepermitted.Thestudywas performed according to the revised declaration of Helsinki for biomedical researchinvolvinghuman subjectsand therules of GoodClinicalPractice.Theinvivobioavailabilitywascarriedout underthebioequivalenceguidelines(KFDA2008-25)accordingto theKoreanFood&DrugAdministration.Theeightvolunteerswere randomlydividedintotwogroups
The current controlled release tablets containing SESD and marketedDynacicr®capsulesequivalentto5mgIDPwereorally giventohumanvolunteerswith250mLofwaterforcomparatibe bioavailability.Foodanddrinkswerewithheldforatleast4hafter dosing.Standardizedlunchanddinnerwereserved5hafterdosing Allsubjectswereprohibitedfromstrenuousactivityand consum-ingalcoholicdrinksduringthestudy.Bloodsamples(10mL)were withdrawnthroughanindwellingthree-waycatheterinthe fore-armandcollectedinheparin-loadedvacutainersat0,0.5,1,1.5,2,
3,4,6,8,10,12,24and36hafterdosing.Thebloodsampleswere centrifugedfor10minat3000rpm.Thecollectedsampleswere keptfrozenat−70◦Cuntilanalysis.
2.3.2 AssayofIDPinhumanplasma TheLC/MS/MS systemwas usedfor theanalysisofIDP.The LC/MS/MS system consisted of the HPLC (PerkinElmer Series
200,Boston, USA),theautosampler(CTCanalyticSPA,Zwingen, Switzerland),theMS/MS(AppliedBiosystemsAPI4000,Boston, USA), and the column (Capcell PAK UG120, 2.0mm×150mm, 5.0mporesize).Themobilephaseconsistedof20%1mM ammo-nium acetate and 80% acetonitrile (pH 6.0 with acetic acid) Felodipinewasusedasaninternalstandard.Theflowrateofthe mobilephasewas0.2mL/min
ForanalysisofIDPinhumanplasma,300Lofplasma,50L (20ng/mL) of internal standard and 30L of 10% ammonium hydroxidewereputintotesttubeandmixed10s.Twomillliliters
ofethyletherwasthenaddedandmixedfor20min.Theresulting solutionwascentrifugedat1500rpmfor5min.The20Lofthe supernatantlayerinjectedtotheLC/MS/MSsystem
2.3.3 Pharmacokineticanalysis Non-compartmentalpharmacokineticanalysiswasperformed ThemaximumplasmaconcentrationofIDP(Cmax)andtimetoreach
Cmax(Tmax)aftertheoraladministrationweredirectlydetermined fromplasmaconcentration–timecurves.Theareaundertheplasma concentration–timecurve(AUC0–36h)fromzeroto36hwas com-putedusingthelineartrapezoidalrule.Alldatawereexpressedas mean±S.D
2.3.4 Statisticalanalysis Logarithmically transformed or untransformed (arithmetic) AUC0–36h andCmaxwas usedfor statisticalanalysisof variance (ANOVA)usingSPSS®forwindowssoftwareandK-BEtest® pro-gram, respectively The drug,period, group and subject nested withingroupwereincludedinstatisticalmodel.TheTmaxwasalso analyzedasareference
Allstatisticalcalculations wereperformedat 5%significance level The confidence interval of pharmacokinetic parameters between the two preparations was allowed within 80–125%
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wa ter pH 1.
2
pH 6.8 Br ij-9 7
Br ij- 9 8
Br ij- 5 8
Br ij- 3 5
crem opho
r E L
crem opho
r RH 40SLS
Tw ee n-8 0
Tw ee n-6 0
Tw ee n-20 tri ace tin
PE
G-600 0
PE
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Ge luc ire 50 /13
cabopo l-934 p
po loxa
me r40 7
po loxa
me r18 8 gly cel in olei c ac id
lin ole
ic id
ca pry lic ac id
ca pr ic id
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500
600
700
Fig 1.The solubility of IDP in various pharmaceutical excipients.
(logarithmicvalue)or80–120%(arithmeticvalue)for
bioequiva-lence,respectively
3 Results and discussion
3.1 Solubilitystudy
Theeffects ofpH,solubilizersand fattyacidondrug
solubil-itywereinvestigatedat 37◦C asshown inFig.1.Thesolubility
ofdruguponvariouspHconditionswasverylow.On theother
hand,allofthesurfactantsandco-surfactantsingeneralhada
ten-dencytoenhancethedrugsolubility.Especially,surfactantssuch
astriacetin,Brij98,SLSandPOX407showedtheirpotential
capa-bilityofenhancingdrugsolubilityremarkably.Becausesolubility
ofIDPinPOX407wasabout1200timeshigherthanthatinwater,
itwasincludedintheSESDformulationsasagoodcarrier.Besides,
othercarrierssuchasPEG6000,PVPK30andGUC50/13werealso
comparedintheSESDformulations
3.2 EffectofformulationcompositionsinSESDsondrug
dissolutionrate
3.2.1 Effectofcarriers
Theeffectofcarriertypesondrugdissolutionratein
intesti-nalfluid(pH6.8)isshowninFig.2.Dissolutionrateofpuredrug
wasverylow(<0.1ppm)inintestinalfluid,confirmingthepoor
watersolubilityofIDP.ThePOX407basedSESDshowed
signifi-cantlyhigherdrugdissolutionrateascomparedtoPEG,PVPand
GUC-basedSESDs.Thisresultwasmatchedwiththepreliminary
studyinwhichsolubilityofIDPreachedthehighestwithPOX407
POX407hasbeenwidelyusedasa wettingand solubilizing
agenttoenhancethesolubility,dissolutionandbioavailabilityof
manypoorlywater solubledrugs(CollettandPopli,2000;Vyas
etal.,2009).TheeffectofPOXcontentondrugdissolutionrate
fromSESDinintestinalfluid(pH6.8)wasalsoinvestigated(Fig.S1)
ThedissolutionrateofIDPsignificantlyincreasedastheamountof
POX407increasedfrom30mgto60mg(SD4-7)duetoitshigh
solubilizingcapability(Leeetal.,2008).Forthisreason,SD4with
thehighestcontentofPOX407(60mg)wasselectedasanoptimal
formulationforfurtherexperiments
Time (min)
0 20 40 60 80 100
raw I DP po wder SD1: PE G-600 0 SD2: PVP K30 SD3: Gelucire 50 /13 SD4: po loxa mer 40 7
Fig 2. The effect of carriers on the dissolution rate of drug from SESD in simulated intestinal fluid (pH 6.8).
3.2.2 Effectofsurfactantandfattyacid Togetherwiththecarrier,incorporatingsurfactantsandother solubilizerssuchasTriacetin,Brij98andoleicacidwerealso impor-tantcomponentstoformnanoemulsionswhenSESDswasexposed
toaqueoussolution.Althoughthesolubilityofdruginoleicacid wasnotsomuchhigh,thisfattyacidwasincorporatedintheSESD formulationbecauseithasbeenknowntobeeffectiveinincreasing
invivoabsorptionandbioavailabilityofpoorlywater-solubledrugs
byformingchylomicronsinthegut(Caliphetal.,2000;Porterand Charman,2001;Parketal.,2007).Figs.S2–S4showdrug disso-lutionratein simulatedintestinalfluid(pH 6.8)asthecontents
ofTriacetin, Brij98and/oroleic acidwerevariedintoPOX 407 basedSESDformulations,respectively.Astheamountofdrug,POX, Brij98andoleicacidwerekeptconstant,therewasnosignificant differenceindrugdissolutionrateofSESDswith(SD4)or with-outtriacetin(SD8)(Fig.S2).Thus, tricetinwasnotimportantin increasingdrugdissolutionandexcludedintheoptimal formula-tion.DrugdissolutionfromSD8(5mgBrij98)wasalmostidentical irrespectiveoftheamountofBrij98ascomparedwithSD9(10mg Brij98)(Fig.S3).So,theamountofBrij98at5mgwassufficient
tomodulatethedrugdissolutionrate.Then,oleicacidwasadded intoSESDformulationtoinvestigatetheeffectofthefattyacid Fig.S4showsthatthepresenceofoleicacidwasnotmeaningful becausedrugreleaseratefromSD8(withOA)andSD10(noOA) wasalmostthesame.Thefactthatdrugdissolutionprofilesfrom thoseSESDswerealmostidenticalwasbelievedduetothegreat effectofPOX407ontheenhancementofdrugrelease.So,the con-tributionofvaryingamountofsurfactantsorfattyacidsinSESD formulationshadanegligibleeffectondrugdissolutionrate Inter-estingly,thedrugdissolutionratefromPOX407basedSESDalone withoutincorporatingsurfactantandfattyacid(SD11)wasthe low-estascomparedwithSD8containingthesetwocomponents(Fig S5).Inotherwords,thedrugdissolutionratewasmainlygoverned
byincorporatingsurfactantinPOX407basedSESD.The dissolu-tionrateofSD4,SD8,SD9andSD10exceptSD11usingPox407 werealmostidentical.However,thefattyacid(OA)andsurfactant (Brij98)werecombinedtoaddintothecurrentPOX407based SESDforfurtherstudiesnotonlyfor enhancingdissolutionrate butalsopromotinginvivobioavailability.Itwasalsoknownthat
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Temperature
0 20 40 60 80 100 120 140 160 180
-10
-8
-6
-4
-2
A 0
B C D E
Fig 3.DSC thermograms of (A) IDP, (B) poloxamer 407, (C) SD11, (D) SD9 and (E)
SD8.
unsaturatedfattyoillikeoleicacidmightenhanceabsorptionand
bioavailabilityofdrugbyincreasinglipophilicityofdrug,oreven
lymphaticabsorptioninPeyer’spatchbyformingchylomicronsin
thegut(PorterandCharman,2001;Parketal.,2007)
3.2.3 Effectoftemperature
InordertoimprovetheprocessingofSESDsintosoliddosage
formliketablet,itisdesirablethatSESDshouldpossessgood
flowa-bilityandcompressibilityproperties.Thus,theadsorbentAerosil®
200waschosenandaddedintotheformulationoftheSESDusing
meltingmethod.Inaddition,becausetemperatureisanimportant
factortocontrolthephysicochemicalpropertiesofSESDprepared
bymeltingmethod(Fassihietal.,1985),SD8waspreparedattwo
differenttemperatures:A–thetemperatureusedinthestudyand
anotherB–lowertemperatureusedforonlycomparisonand
abbre-viatedas SD8lowT◦.Fig.S6shows theeffectoftemperatureson
drugdissolutionratefromSESDs(SD8andSD8lowT◦)insimulated
intestinalfluid(pH6.8).Thedrugdissolutionratewassignificantly
increasedastheheatingtemperatureincreasedfromBtoA
There-fore,thetemperatureAwasconfirmedtobetheoptimalonefor
preparationofSESDsbymeltingmethod
3.3 PhysicalcharacterizationofSESDs
Inordertoelucidatetheenhanceddrugdissolutionratefrom
SESDs,thephysical statesoftheSESDswereinvestigatedusing
instrumentalanalysissuchasSEM,PXRDandDSC(Francoetal.,
2001).IthasbeenwidelyknownthattheSESDcanimprovethe
dissolutionrateofpoorlywater-solubledrugsbychangingthe
crys-tallinestructureofdrugintoahighenergystate,i.e.anamorphous
state.DSCthermogramsofSESDs(SD8,SD8lowT◦ andSD11)are
compared withthepure drugand POX 407in Fig.3 PureIDP
andPOX 407exhibitedsingleendothermicpeaksat169◦C and
52◦C,respectively,whichcorrespondedtotheirintrinsicmelting
points.Incontrast,thethermogramsofallSESDsshowedthatdrug
characteristicpeakdisappearedexceptforthatofthecarrieritself
indicatedthatmostofcrystallinedrugchangedintoitsamorphous
structure(LeunerandDressman,2000).Thisfactwasattributed
tobeafactorenhancingdrugrelease.However,additionalpeaks
werealsoobservedaround50–55◦CincaseofSD8lowT◦andSD11
Itsuggesteddrugwasnotcompletelyamorphous,givingdecreased
dissolutionrateasshownpreviously
0 500 1000 1500
2000
A
B C D E F
Fig 4.The powder X-ray diffraction patterns of (A) IDP, (B) poloxamer 407, (C) SD11, (D) SD9, (E) SD8, and (F) Aerosil ® 200.
ThePXRDpatternsofSESDs(SD8,SD8lowT◦andSD11)arealso comparedwiththepuredrugandPOX407inFig.4.Diffractogram
ofthepuredrugrevealsthehighlycrystallinenaturethroughits numerous distinctivepeaks POX407 aloneexhibited two high intensitypeaksat18◦ and 24◦.Contrarily,numerousdistinctive peaksofthedruginthethreeSESDsdisappeared,indicatingthat
ahighconcentrationofthedrugwasdissolvedinthesolid-state carriermatrixinanamorphousstructure(Sheenetal.,1995;Hu
etal.,2003).TherewasnosignificantdifferenceinPXRDpatterns amongSESDsystems(SD8,SD8lowT◦andSD11)
InadditiontophysicalstateofdruginSESDsystem,either amor-phousorcrystallinestructure,theimaginganalysisusingSEMwas examinedtoclarifythedifferencesindissolutionprofilesamong SESDformulations.ThesurfacemorphologyofIDPpurematerial, POX407,Aerosil®200,SESDs(SD8,SD8lowT◦andSD11)isshown
inFig.5.IDPcrystalshaveanacicularformwhereasPOX407and Aerosilshowedirregulargranuleshapeandpowder-likespherical shape,respectively.TheSESDsappearedtobeirregularly granu-latedoragglomerated,dependingonthepreparationtemperature andformulationcompositions.Thesedifferencesofmorphological propertiescanaffectphysicalstateofdrugandwettabilityofSESD, varyingdrugdissolutionrate.SD8lowT◦,preparedbythemelting methodatlowtemperature,orSD11withoutanysurfactantand fattyacid,exhibitedcrystallinestateofdrugintheSESD,resulting
indecreaseddissolutionrateasdiscussedpreviously.Meanwhile, theSD8showedalmostamorphousstructure,indicatingthedrug dissolutionenhancementwasduetothelackofcrystallinestate andthebetterwettability
3.4 EffectofHPMCcontentondissolutionrateofcontrolled releasetablet
TheoptimallyformulatedSD8wasusedtopreparecontrolled release HPMC matrix tablet Hydrophilicswellable HPMC poly-mersarewidelyusedtocontrolthereleaseofdrugsfrommatrix formulations(Alderman,1984;Raoetal.,1990).Additionally, cel-luloseethershavegoodcompressioncharacteristicssothatthey canbedirectlycompressedtoformswellable sustainedrelease matrices (Doelker,1987) Thepolymer content and the viscos-ity grade of HPMC are considered tobe critical factors in the controlledreleaseofdrugsduetothechangesofswelling behav-iorsofHPMCmatrices(Bonferonietal.,1998;Katzhendleretal., 2000; Caoet al., 2005).Therefore, the effectof HPMC quantity
ondissolutionrateofthecontrolledreleasedHPMCmatrixtablet
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Fig 5. SEM photo-micrographs of IDP (× 10k), poloxamer-407 (× 2k), Aerosol 200vv (× 10k), SD8 (× 10k), SD9 (× 10k) and SD11 (× 10k).
in simulated intestinal fluid (pH 6.8) was investigated (Fig.6)
Thehardnessand friability of HPMC matrix tabletswere given
40.0±5N and 0.3±0.05% respectively The matrix tablet
with-outHPMC(T1)orhavinglowcontentofHPMC(T2)displayeda
rapiddisintegrationwithnocontrolledrelease.TheHPMCmatrix
tabletsshowedcontrolledreleaseoveraperiodof10–16h
depend-ingontheHPMCcontent(T3–T6)becauseoftheswellingproperty
ofHPMCasreportedonsomewhere(Wanetal.,1993;Pateland
Patel,2007).OneofthemostimportantcharacteristicsofHPMC
isthe highswellability, whichhas aconsiderable effectonthe
releasekineticsofincorporateddrugs(Velascoet al.,1999;Cao
etal.,2005).WhenHPMCmatricescome incontactwithwater
or aqueous gastro-intestinal fluids, the polymer absorbs water and undergoes swelling and hydration The rapid formation of
a viscous gel layer upon hydration has been regarded as the essential step in achieving controlled drug release from HPMC matrices.Thisprocessleadstorelaxationofthepolymerchains withareductionintheglasstransitiontemperatureofthe poly-mer Subsequently, thepolymer undergoes a glassyto rubbery phasetransitionandthepolymericchainsdisentangleasaresult
ofincreaseddistanceseparationbetweenthechainstodiffusethe drugmoreeasily(Parakh etal.,2003).Contrarily,themarketed Dynacirc® capsuleshowed verylow dissolution rate(T0;about 20%/24h)
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Time (h)
0
20
40
60
80
100
T0: Dynac irc Capsule T1: HPMC 0 % T2: HPMC 5 % T3: HPMC 10 % T4: HPMC 20 % T5: HPMC 25 % T6: HPMC 30 %
Fig 6.The effects of amount of HPMC on the dissolution rate of controlled released
tablet in simulated intestinal fluid (pH 6.8).
3.5 Stabilitystudyofcontrolledreleasedmatrixtablet
Drugdissolutionratesfromthecontrolledreleasematrixtablets
(T4–T6)arealmostidentical.T4withloweramountofHPMCwas
consideredastheoptimalformulationtoavoid stickiness
prob-leminthetabletingprocess.ThestabilityofHPMCmatrixtablet
(T4)containingSESDwasalsoinvestigatedundertheaccelerated
storageconditionsorroomtemperature.Releaseprofilesof
con-trolledreleasedHPMCtabletsinsimulatedintestinalfluid(pH6.8)
asa functionoftimeunderthetwodifferentstorageconditions
areshowninFig.7.Thedissolutionprofilesofthetabletsattwo
differentstorageconditionswerealmostidenticalfor3months
Time (h)
0
20
40
60
80
100
Initial
1 mo nth s: 40 degree / 75 % RH
1 mo nth s: Ro om temp erature
3 mo nth s: 40 degree / 75 % RH
3 months: Room temperature
Fig 7.Dissolution profiles of controlled released tablet in simulated intestinal fluid
(pH 6.8) as a function of time during various storage conditions.
Time (h)
0 1 2 3 4 5
Dinacirc-Reference
CR Table t (T4)
Fig 8.Plasma concentration–time profiles of IDP after an oral administration of controlled released tablet (T4) and marketed Dynacirc ® capsule in healthy human volunteers.
ascompared withinitialtime Moreover,the drugcontentwas almostunchangedduringstorageconditionsfor3months(data notshowed).Accordingly,theHPMCmatrixtabletcontainingSESD (T4)inthestudyhasagoodstabilityandcouldbeusedtodelivery poorlywater-solubleIDPinacontrolledmanner
3.6 Pharmacokineticbehaviorsofcontrolledreleasetabletin healthyhumanvolunteers
Theplasmaconcentration–timeprofilesofcontrolledreleased HPMCmatrixtablets(T4)andmarketedDynacirc®capsule equiv-alentto5mgofIDPfollowinganoraladministrationtohealthy humanvolunteersareshowninFig.8.TheTable3alsocompares pharmacokineticparametersofIDPbetweencontrolledreleased matrixtablets(T4)andmarketedDynacirc®capsule.Thecontrolled releasedHPMCmatrixtabletsshowedsignificantlyincreasedCmax andAUCcomparedtothemarketeddynacirc® capsule.The rel-ativeAUCand Cmaxof controlledreleasedHPMCmatrix tablets increasedabout256%and587%,respectively.Duetothe solubi-lizationeffect,theTmaxofcontrolledreleasedHPMCmatrixtablets wasalsohighlyadvanced.Themechanismforthisenhancedinvivo bioavailabilityresultedfromthecontrolledreleaseofhighly solu-bilizableSESDsystemloadedinHPMCmatrixtablet.Asthewater penetratesintothetablet,drugreadilydissolvesviaemulsification processandreleasethroughthepolymericnetworkofHPMCina controlledmanner.Thechangeofdrugcrystalstructureinto amor-phousformaswellastheincreaseofwettingandsolubilization
Table 3
Comparison of pharmacokinetic parameters after an oral administration of con-trolled released matrix tablets (T4) and marketed Dynacirc ® capsule equivalent to
5 mg IDP in healthy human volunteers.
No AUC (ng h/mL) C max (ng/mL) T max (h) Dynacirc ® 8.56 ± 4.28 0.48 ± 0.10 8.25 ± 3.86 *
* p < 0.05, significantly different compared to Dynacirc ®
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capacitybyincorporatingexcipientsortheirmixtures(surfactant
andfattyacid)intotheSESDsystemcouldcontributetheenhanced
dissolutionofIDPasdiscussedpreviously
4 Conclusions
TheSESDpreparedbymeltingmethodcouldbeauseful
formu-lationtoenhanceinvitrodissolutionandinvivobioavailabilityof
apoorlywater-solubledruglikeIDP.Thedissolutionenhancement
inSESDsystemwasattributedtothechangeofdrugcrystalline
intotheamorphousstateandtheformationofmicroenvironment
todissolveIDPbyincorporatingformulations.ThisSESDsystem
wasdispersedinHPMC-basedmatrixtablettocontroltherelease
rateofdrug.Interestingly,theHPMCmatrixtabletcontainingSESD
showedgoodstability andenhanced invivobioavailability The
drugcontentanddissolutionprofilesofthetabletswereunchanged
duringstoragefor3months.Oralbioavailabilityofthecontrolled
releaseHPMCtabletwashighlyincreasedascomparedwiththe
referencecapsuleinhealthyhumanvolunteers.Therefore,
solubi-lizationmethodcombinedwithcontrolledreleasetechniquecould
provideauniquewaytoincreasedissolutionrateand
bioavailabil-ityofmanypoorlywater-solubledrugs
Acknowledgements
ThisworkwassupportedbyagrantfromtheKoreanHealth
TechnologyR&DProject,MinistryforHealthandWelfare,Korea
(A092018).WewouldliketothanktheCentralResearchLaboratory
fortheuseoftheDSC,PXRDandSEM,KangwonNationalUniversity
Appendix A Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.ijpharm.2013.04.022
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