2.2.Methods 2.2.1.PreparationofSDs MeltingmethodwasusedforpreparationofSDs.Followingare some factors that were varied to prepare different SDs for evaluation of drug release rate: swella
Trang 1Pharmaceutical nanotechnology
Tuong Ngoc-Gia Nguyena, Phuong Ha-Lien Trana,* , Thanh Van Tranb, Toi Van Voa,
Thao Truong-DinhTrana,*
a
Pharmaceutical Engineering Laboratory, Biomedical Engineering Department, International University, Vietnam National University, Ho Chi Minh City,
Vietnam
b School of Pharmacy, University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam
A R T I C L E I N F O
Article history:
Received 6 November 2014
Received in revised form 20 February 2015
Accepted 27 February 2015
Available online 28 February 2015
Keywords:
Solid dispersion
Melting method
Swellable polymer
Poorly water-soluble drug
Controlled release
A B S T R A C T
1.Introduction
Solid dispersion (SD) is a potential approach in enhancing
dissolution and bioavailability of poorly water-soluble drugs
Advantagesof thetechniquesuchas simplicity,economization,
andothershavebeenwidelyreported(Vasconcelosetal.,2007)
TherearetwobasicdifferentpreparationmethodsofSDincluding
meltingmethodandsolventevaporationmethod(Tranetal.,2009,
2010).MeltingmethodwasfirstdemonstratedbySekiguchiand
Obi(1961).Theproductwaspreparedbymeltingdrugwithcarrier,
then cooling and pulverization In the melting process, high
mobilityof carrierwould changethecombinationof drug(van
Drooge et al., 2006).In solventevaporation method, drug and
carrierwere completelydissolved in a volatilesolvent suchas
ethanol,chloroform,oramixtureofethanolanddichloromethane
(Hasegawaetal.,2005;Lloydetal.,1999;Rodieretal.,2005)ata
lowtemperaturetoavoidthermaldegradationofdrugandcarrier
(Wonetal.,2005).Thelatermethodhassomedisadvantagessuch
ashighpreparationcost,incompletesolventremoval,alterationin product performance with the change of condition applied (Vasconcelosetal.,2007)
Theswellablehydrophilicpolymershydroxypropyl methylcel-lulose(HPMC)andpolyethyleneoxide(PEO)wereintroducedin thisstudytomodulatedrugreleasefromaSD(Tranetal.,2011; TranandTran,2013).Astheyarehydrophilic,thesepolymersmay improve thesolubilityof poorly water-solubledrugs, and their swellablepropertiesmaybeexploitedtopromotecontrolleddrug release Theutilization of thesetwo polymerproperties inone system might facilitate the development of specialized drug deliverysystemsbybothenhancingdrugsolubilityandcontrolling the release of poorly water-soluble drugs Thishypothesis was tested herein through the preparation of SDs However, these polymers are difficult to melt at high temperatures for SD preparation On the otherhand, disadvantagesare usually met
inthesolventmethodasmentionedabove.Moreover,drugsmay
beprecipitatedduringsolventremoval,leadingtothefailureofthe methodintendedtoenhancedrugsolubility.Slowdrugdissolution ratesresultwhenthedrugsarenotwelldistributedinthepolymer Therefore,theSDmethodisnotalwaysasuccessfulapproachto
* Corresponding authors Tel.: +84 8 37244270x3328; fax: +84 8 37244271.
E-mail addresses: thlphuong@hcmiu.edu.vn (P.H.-L Tran),
ttdthao@hcmiu.edu.vn (T Truong-DinhTran).
http://dx.doi.org/10.1016/j.ijpharm.2015.02.064
0378-5173/ã 2015 Elsevier B.V All rights reserved.
ContentslistsavailableatScienceDirect
j o u r n al h o m ep a g e: w w w el s e v i e r c o m / l o c at e / i j p h a r m
Trang 2meltingmethodwasdevelopedasanewfeasibletechniqueusing
swellable hydrophilicpolymers.The system was fabricatednot
onlytoincreasethedissolutionratesofpoorlywater-solubledrugs,
butalsotopotentiallycontrolthereleaseofthosedrugs.Curcumin
(CUR),apoorlywater-solubledrugwithmanypotential
applica-tions,was usedasthemodeldruginthis study.Thecrystalline
behaviors and molecular interactions in the system were
investigatedtoelucidatethepotentialofthissystem
2.Materialsandmethods
2.1.Materials
Curcuminandsodiumhydroxide(NaOH)werepurchasedfrom
Guanghua Sci-Tech Company (China) Hydroxypropyl methyl
cellulose(HPMC 4000, HPMC6) and polyethyleneoxide N-60K
(PEO) was provided by from Dow Chemical Company (USA)
Polyethyleneglycol(PEG 6000) waspurchased fromSino-Japan
Chemical(Taiwan).Methanol(MeOH)waspurchasedfromFisher
Scientific International, Inc (US) Hydrochloric acid (HCl) and
sodium chloride (NaCl) were purchased from Xilong Chemical
Industry Incorporated Company (China) Monopotassium
phos-phate (KH2PO4) was purchased from Wako Pure Chemical
Industries(Japan)
2.2.Methods
2.2.1.PreparationofSDs
MeltingmethodwasusedforpreparationofSDs.Followingare
some factors that were varied to prepare different SDs for
evaluation of drug release rate: swellable polymers (HPMC 6,
HPMC4000,andPEO),thepolymerratio,andcombinationmethod
betweendrugandpolymers(Table1).TheSDswerefinallystored
inadryplaceandprotectedfromlightuntilfurtheruse
Twocombinationmethodsweredifferentiatedbytheorderof
incorporation of drug and swellable polymer into melted PEG
6000.InmethodI,PEG6000anddrughadbeenthoroughlymixed
beforethe polymer was added in the mixture PEG 6000 was
meltedat190C,andCURwasthenaddedunderstirringuntila
uniformmixturewasobtained.Thentheswellablepolymerwas
dispersedinthemixturetoobtainSDsinsemisolidformwhich
werefinally cooledat room temperature(25C) before use In
methodII,PEG6000andswellablepolymerweremixedbeforethe
drugwasadded intothemeltedmixture.Every otherstepwas
conductedasit wasin methodI.The meltingtemperaturewas
controlledandthemixturewasstirredondigitalstirringhotplates
(ThermoScientific,Germany)duringthepreparationprocess
2.2.2.Dissolutionstudies
DrugdissolutionwasstudiedwithSDsat370.5C(50rpm,
paddleapparatus,DT70Pharmatest, Germany)accordingtothe
USP30pharmacopoeia.Buffer(pH1.2orpH6.8,900mlineach dissolutionvessel)wasusedasthedissolutionmedium.Sample aliquots (1ml)werecollectedfromthemediaatpredetermined intervalsof 10, 20, 30, 60, 90, and 120min.1ml ofwithdrawn sample was compensated byadding 1ml of thecorresponding freshbuffer
2.2.3.HPLCanalysis The quantificationof CURwas performed usingan Ultimate
3000HPLCsystem(ThermoscientificInc.,USA).Themobilephase was4:1methanol/aceticacid2%.Theflowratewasmaintainedat 1.2ml/min.TheUV/visdetectorwassettoawavelengthof425nm
20mlofsamplewasinjectedtoHPLCsystem
2.2.4.CharacterizationbyX-raydiffraction(PXRD)
In this study, pure CUR, PEG 6000, HPMC 4000, physical mixture(PM),andSDswereanalyzedbyPXRD.Diffractionpatterns were recorded by a Powder X-ray diffractometer (Bruker’ D8 Advance Series PXRD, Germany) using Ni-filtered, CuKa
(l=1.54060Å)radiationatavoltageof40kVandatacurrentof
40mA Samples were held on quartz frame The sample was scannedina2ufrom5to50withareceivingslit0.1mm(astep sizeof0.021at2u/s)
2.2.5.CharacterizationbyFouriertransforminfraredspectroscopy (FTIR)
ThephysicochemicalpropertiesofCUR,PEG6000,HPMC4000,
PM,andSDswerecharacterizedbyusingaBrukerVertex79FTIR spectrometer (Germany) KBr pellets were prepared by mixing
1mg of samples with 200mg KBr The wavelength was 500–
4000cm1andtheresolutionwas2cm1 2.2.6.Solubilitytest
ExcessCURwasaddedtothetubescontaining1mlofvarious media(pH1.2andpH6.8).Theresultingmixtureswereshakenat
100rpmat37C for48hina waterbath.Thetubes werethen centrifugedat13,000rpmfor15min.Thesupernatantwasdiluted forthedeterminationofdrugconcentrationbyHPLC
2.2.7.Statisticalanalysis All data were presented as meanstandard deviation The statisticalsignificanceofthedifferenceswasdeterminedusingan analysisofvariance(ANOVA)(P<0.05or0.01)
3.Resultsanddiscussion 3.1.Dissolutionandsolubilitystudies OurpreliminarystudyshowedthatCURwaspoorlysolubleand had lower solubility in acidic medium than basic medium Specifically, solubility of CUR at pH 1.2 and pH 6.8 were 7.2300.35and12.6233.54,respectively.Forthisreason,most Table 1
Formulation compositions of SDs.
Formulation Cur (mg) PEG 6000 (mg) HPMC 4000 (mg) HPMC 6 (mg) PEO (mg) Ratio Mass (mg) Stirring time Combining method
T.N.-G Nguyen et al / International Journal of Pharmaceutics 484 (2015) 228–234 229
Trang 3intestinalfluid(pH6.8)wasfasterthanthatingastricfluid(pH1.2)
andthepercentageofpureCURreleasedinthesemediawasunder
5% in previous studies (Tran et al., 2015) Therefore, the
improvementofdissolutionrateintheseconditionswas
discov-ered.Fig.1showstheeffectofpolymertypeontheCURdissolution
rateinpH1.2andpH6.8media.Inthefirst10min,thedissolution
ratesofF3(HPMC6)andF5(PEO)tendedtobegreaterthanthatof
F4(HPMC4000)inbothmedia.However,thedissolutionrateof
F5decreased after20min,and onlyasmall percentageofdrug
(around5–8%)wasreleasedfromtheformulationintheremainder
ofthe experiment.Meanwhile, after30min,F3clearlyhad the
highestdrugreleasewhich(17.3%and12.9%atpH1.2andpH6.8,
respectively).Unexpectedly,thedissolutionprofileofF3exhibited
a “spring-like” phenomenon (Tran et al., 2009) due to drug
precipitationfrom60minonwardsinbothmedia;incontrast,for
F4,drugreleaseincreasedcontinuouslywithincreasingtimeinthe
media.After2h,F4clearlyhadthehighestdrugrelease(17.7%and
18.6% at pH 1.2 and pH 6.8, respectively) Therefore, HPMC
4000 was selected for further study This result is interesting
becausedrugreleaseisexpectedtobeslowerinthepolymerwith
higherviscosity.Inthisstudy,HPMC4000hasahigherviscosity
thanHPMC6,whichmayhavebeenanadvantageofHPMC4000by
preventingdrugprecipitation(Warrenetal.,2010)
LeunerandDressmanprovedthatoneofthemaininfluenceson
efficiency of a SD in increasing drug dissolution is the ratio between drug and carrier (Leuner and Dressman, 2000) The excessivedrugamountinSDwilltendtoformmoresmallcrystals within the dispersion than maintain molecularly dispersed (LeunerandDressman,2000).Ontheotherhand,thecrystallinity
ofthedrugwillcompletelydisappearinthecasewherethehigh percentageofcarrierisused,whichleadstoamassiveincreasein solubility and dissolution rate of drug (Leuner and Dressman,
2000).ExperimentswereconductedwithdifferentCUR:PEG600: HPMC 4000 ratios to determine which formulation most effectivelyincreaseddrugdissolution Fig.2 showsdrugrelease fromdifferentformulations(CUR:PEG600:HPMC4000ratiosof 1:4,1:8,1:4:2,1:4:4,1:8:4,and1:8:6,correspondingtosamplesF1, F2,F4,F6,F7,andF8,respectively)basedonmethodI.Thehighest percentageofdrugreleasefromF1,F2, F4,F6, F7,andF8atpH 1.2was26.3%, 16.17%, 17.7%,13.29%,38.3%,and29.31%,respectively Meanwhile,thehighestpercentagedrugreleaseatpH6.8were 18.53%,17.07%,18.6%,18.93%,42.83%,and29.82%,respectively.A muchhigherpercentageofdrugwasreleasedforF1comparedto F2,indicatingthatthehigherpolymerconcentrationresultedina slower drug release For the higher amount of polymer, the formulation took longer to dissolve due to the longer water penetrationprocess.ThepercentagesofdrugreleasedfromF1and F2graduallydecreasedafter20min,predominantlyasaresultof
Fig 1 Dissolution profiles of CUR from SDs of F3, F4 and F5 based on types of
polymer as a function of time in gastric fluid (pH 1.2) (A) and intestinal fluid (pH 6.8)
Fig 2 Dissolution profiles of CUR from SDs of F1, F2, F4 and F6 to F8 based on polymer ratio as a function of time in gastric fluid (pH 1.2) (A) and intestinal fluid
Trang 4percentagedrugreleaseofF1andF2after2hwerearound14.3%
and 12.5% at both media respectively, decreasing from 1.3 to
1.8 foldas compared totheirhighest percentagedrug release)
However,thecombination ofPEG6000andHPMC 4000inSDs
gave goodresults F7exhibitedthe highest percentage of drug
release at pH 6.8 (about 42.83%; Fig 2B) Despite a little
precipitationafter60min,F7was still farbetterin comparison
to other formulations Nevertheless, increasing the amount of
HPMC4000didnotresultinahigherpercentageofdrugrelease
So,inmethodIF7preparedattheratio1:8:4ofCUR:PEG6000:
HPMC4000waschosenasthebestSDformulation
However,becausethedissolutionratesofSDformulationswere
still low(below 50%),a newmethodshouldbe investigatedto
increasethepercentageofdrugrelease.Dissolutionand
bioavail-ability of poorly water-soluble drugs can be enhanced by
stabilizing the drugs in its amorphous state Permutation of
introduction of carriers into the formulation may lead to
modification of physicochemical properties of drug It was
expectedthatthenewapproachwouldincreasedissolution,and
hence, bioavailability of CUR By applying the permutation of
carriers,thepercentageofdrugreleaseinmethodIIwasincreased
2foldcomparedtomethodI.Whilethepercentagesofdrugrelease
obtainedusing method Iwere 42.8% and 29.8% for F7 and F8,
respectively,thepercentageofdrugreleaseobtainedusingmethod
IIreached82%and62.6%forF9andF10,respectively(seeFig.3A
and B) These resultssuggestedthat method IIproduced more
amorphous form than method I The influence of amorphous
versuscrystallineformsondrugdissolutionwouldbeexplained
clearer by FTIR and PXRD characterization in the following
sections A large amount of HPMC 4000 in the formulation
generallyreducedthedrugdissolutionrate.F9andF10dissolved
betterthanF7andF8,resultingintransparentsolutions.However,
thefactthatF10seemedtohavemoresedimentafter2hcompared
toF9couldexplainwhyF9dissolved betterthanF10.Probably
redundantHPMC4000existedinsolutioncouldnotfullyswell.It
wasalsothereasonwhytheformulationatratio1:8:6(F8andF10)
alwayshadalowerpercentagedrugreleasethantheoneatratio
1:8:4(F7andF9),nomatterwhatcombiningmethodwasapplied
Finally,F9waschosentobetheoptimalmodelofthestudy
In summary, in vitro dissolution tests indicated that PEG
6000canbecombinedwithotherhydrophilicpolymerstoenhance
thedissolutionratesofpoorlywater-solubledrugstopreventdrug
precipitation Interestingly,the combination of a poorly
water-solubledrugwithswellablepolymersinPEG6000-basedSDsisa
promising approachto improvedissolution rates.However, the
moreinterestingpointwasthestepofthecombinationbetween
PEG and drug or thecombination between PEG and HPMC It
playedacriticalfactortoenhancedrugdissolutionreleasedueto
themodificationofdrugphysicochemicalproperties.The
combi-nationbetweenPEG6000andHPMCshouldbeconductedbefore
addingdrug(methodII)foradoublestrengthactionofdissolving
thedrugandpreventingthedrugrecrystallization.Themolecular
dispersionofpoorlywater-solubledrugsinhydrophilicpolymers
ofSDswouldformahighsurfaceareaofdrugandreducedparticle
sizewhichpromotedthedissolutionenhancementandhence,led
toincreasedbioavailability(Vasconcelosetal.,2007).Moreover,
ratioamongthecomponentsof theformulationswasalsovery
important Effects of those factors ondrug dissolution profiles
wouldbeelucidatedmorethroughPXRDandFTIRstudies
3.2.Effectsofcombinationmethodandpolymerratioondrug
crystallinityandmolecularinteraction
TheXRDpatternsofX-raypureCUR,PM,andSDsofF4,F7,and
F8 are shown in Fig 4A to demonstrate effect of different
formulations ondrugstructure TheXRDpatterns ofF7, F8,F9, andF10areprovidedinFig.4Btoillustratetheeffectofdifferent combination methods on drugstructure Amorphous statewas indicated by the disappearance of distinctive peaks or a large reductioninnumberofcharacteristicpeaksindiffractograms(Tran
etal.,2008).ThediffractionpatternofpureCURshowednumerous peaks,indicatingthehighlycrystallinenatureofthedrug.PMwas obtainedbythoroughlyblendingpureCUR,PEG6000,andHPMC
4000 at a 1:8:4 ratio, which gave the highest drug release percentage The diffractionpattern of PMretained mostof the characteristic peaks of pure CUR, PEG 6000, and HPMC 4000 However,comparedwithpureCUR,thepeaksat7.8,12.2,18.1,and 28.82uofPMweredisappeared,resultingfromtheinfluenceof amorphousformofHPMC4000.ForthePMsandSDsofF4andF7, althoughmostofthepureCURpeaksdisappeared,thepeaksat 19.1,23.3,26.1,26.9,36.2,39.6,and 42.92uwerestillobserved Nevertheless,thebroadpeaksat13.52udisappearedinthePM spectraofF4andF7.ThisbroadpeakmightbeaffectedbypureCUR
orHPMC4000;thus,itsdisappearancemightindicatethatCUR waswelldispersedinPEG6000,orthatHPMC4000wasalmost completely swelled in PEG 6000, which would promote drug dissolutionandhinderdrugprecipitation.Thecharacteristicpeaks
at 8.9,10.5,14.5,14.9, and 17.2 2u were absent or reduced in
Fig 3 Dissolution profiles of curcumin from SDs of F7, F8, F9, and F10 based on combining method as a function of time in gastric fluid (pH 1.2) (A) and intestinal fluid
T.N.-G Nguyen et al / International Journal of Pharmaceutics 484 (2015) 228–234 231
Trang 5ThisindicatedthatF7wasmoreamorphousthanF4,resultingina
higherdissolutionrate.Althoughthepeaksat26.1,26.9,32.5,36.2,
39.6,and42.92uwereabsentinthespectrumofF8comparison
withthatofF7,abroadpeakat13.52uremainedtheinspectrumof
F8.ThisindicatedthatF8wasinfluencedbythecrystallineformof
pureCURorHPMC4000.Intheexperiment,theamountofPEG
6000inF8wasnotenoughtoswellHPMC4000completely.The
excessiveamountofHPMC4000influencedtheabilityofCURto
disperseinthecarrier,resultinginthedecreaseddissolutionrate
Therefore,F8hadalowerdissolutionratethanF7,eventhoughits
spectrumshowedlesspeaks.AsillustratedinFig.4B,theeffectof
the combination method on the physical structure of the
formulation was evaluated The dissolution test resultsfor the
SDs of F7, F8, F9, and F10 (corresponding to 1:8:4 method I,
1:8:6methodI,1:8:4methodII,and1:8:6methodII,respectively)
showedthatthecombinationmethodcouldchangethedissolution
profileofCUR.AlthoughPMhadthesameratiowithF7andF9,its
diffractionpatternseemedtobesimilarwiththeonesofF8and
F10.ThisresultwasexplainedbythepresenceofHPMC4000or
pure CUR in the physical structure The comparison of two
methods at relative ratios showed that the disappearance or
reductionofpeakswasdetectedat14.5,14.9,17.2,32.5,36.2,39.6,
and42.92uinF9,suggestingthetransformationintoamorphous
form from method I to method II Similarly, the decrease in
intensityofpeakswasobservedat13.5,35.6,36.2,and39.62uin
F10,supportingforthehypothesismentionedabove.Accordingto
thestudy,increasingHPMC4000concentrationdidnotenhance
dissolutionrateofCURduetothelackofPEG6000amountfor
swellingHPMC4000.Therefore,theratio1:8:6alwayshadlower
dissolution rate compared to the ratio 1:8:4 regardless of any
appliedcombiningmethod
InFTIRanalysis,aspecificchemicalbondwasindicatedbythe
presenceofapeakataspecificwavenumber.Theappearanceof
new peaks or a shift of existing peak represented a specific
interactionamong the materials(Liu and Bai, 2005) The FTIR
spectraofpureCUR,PM,F4, F7,andF8areshownin Fig.5Ato
demonstratetheeffectofcompositionalratioonCURdissolution
Bin et al (2013) suggested that the sharp band at around
3500cm1 and the broad peak centered at 3300cm1 in the crystalline spectrum are attributed to phenolic OH stretching The—OHgroupisindicatedbyastrongbandaround2890cm1 The regions from2700–3000cm1 in thespectra of pure CUR, HPMC4000,PEG6000,PM,andSDsexhibitedpeaksassignedto aliphatic C—H stretching (Bich et al., 2009) Strong bands at
1626cm1inthespectraofpureCUR,PM,F4,F7,andF8couldbe assigned to a predominantly mixed C¼C and C¼O character (Mohanetal.,2012).Moreover,theIRbandsat714cm1inthe spectraof these materialscouldbeassigned tocis-C—H outof planevibrationofthearomaticring(Mohanetal.,2012).Nopeak
at1430cm1wasobservedinthespectrumofF8,revealingthe lackofthein-planebendingvibrationofolefinicC—H(Wanetal., 2012; Yadav et al., 2009) The disappearance of the peak at
1514cm1inthespectrumofF7indicatedtheabsenceofthehighly mixedvibrationofC¼OandC¼C(Wanetal.,2012;Yadavetal., 2009;Yallapuetal.,2010).Thedisappearanceofthispeakmightbe caused by the formation of intermolecular hydrogen bonds betweentheO—H groups of PEG6000 and theC¼O groupsof CUR,whichwouldresultintheincreasedsolubility/dissolutionof thedrug(Yenetal.,2010).Thecomparisonoftheseresultswiththe dissolution profilesindicated that F7, which exhibited a better dissolutionrate,couldbeappliedforfurtherstudy
Fig.5Billustratestheinfluenceofthecombinationmethodon theSDsof F7toF10 Incase of F9,thebroad peakcentered at
3300cm1remained,whilethesharpbandataround3500cm1 disappeared.ThispeakmightbeaffectedbypureCURorHPMC
4000.Accordingtothepreparationmethodanddissolutionprofile, HPMC 4000firstlyshouldbecombinedwithPEG6000tohave betterswelling.Consequently,thedisappearanceofphenolpeakin thespectrumofF9mightbecausedbyhydrogenbondinteractions
Inaddition,thespectrumofF9showedanewpeakat1714cm1, indicatingacarbonylgroupsandketonegroupsinparticular(John,
2000).CURwaspresentinatleasttwotautomericformsincluding keto(aC¼OandanadditionalC—Hbond)andenol(anO—Hgroup Fig 4 (A) PXRD patterns of pure Cur PEG 6000, HPMC 4000, PM and SDs of F4, F7 and F8 in different ratio (B) PXRD patterns of SDs of F7, F8, F9 and F10 in different combining method.
Trang 6thepbondoccurredduetotheconjugationbetweentheenolC¼C
andthecarbonylgroup.Moreover,theOHoftheenolgroupcould
formahydrogenbondwiththeoxygenofthenearbyC¼Ogroup
Theseintramolecularhydrogenbondsareespeciallystabilewhen
theyformasix-memberedring(Janice,2010).Therefore,theenol
hydrogen ion (H+) is lost in the process of hydrogen bond
formation
4.Conclusion
HPMC 4000 was demonstrated to bean effectiveswellable
polymer in combination with PEG 6000 for enhancing drug
dissolutionin modifiedSDs.MethodII,inwhichPEG6000 and
HPMC 4000were mixedbefore the drugwas dispersed in the
polymermixture,wasfoundtobethebestcombinationmethodto
achievetheaimofthestudy.Thiscombinationmethodfacilitated
theswellingofHPMC4000,resultingingooddrugdispersionto
changeandmaintaindrugstructuretoamorphousformbutalso
for promotion of some chemical interaction between the
components, leading to increased drug dissolution The
modi-fied-SD would be an alternative approach to solve common
problems ofconventional SDsincluding drugprecipitation and
ineffectiveenhanceddrugdissolution
Acknowledgement
We would like to thank International University, Vietnam
National University, Ho Chi Minh City (SV2013-01-BME) for
partiallysupportingresearchgrant
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