Liu, R.

, 2008, water insoluble drug formulation, Second Edition, CRC

Press, Taylor & Francis, Boca Raton.
Ananosuspensionisasubmicroncolloidaldispersionofpuredrugparticles,whichposse
ssalarge
surfaceareaforenhanceddissolution.Dissolutionrate,dependingonsurfaceareaando
therfactors,Waterinsolubledrugscanbeformulatedasnanoparticleswithhighsurfaceareaandenhanced
dissolutionratesaccompaniedwithreduceddrugparticles.Administeringacompoundass
mallparticles
ofde-nedsizemaybesuperiorto,forexample,acosolventformulation.Inthelattercase,
precipitation,particlesizeoftheprecipitateandsiteofprecipitation
invivoisdif-culttopredictfrom invitro
experiments(Pannutietal.,1987).Assumingdrugparticlesareinanearsphericalshape,
areduction
inparticlesizefrom10 mto200nmincreasesdrugsurfaceareaby50fold,whichmayhaveaprofoundeffectondrugabsorption.Foradrugwithdissolutionratelimitedbioavailability,particlesize
reductioncansigni-cantlyimprovethePKperformanceofthedrug(LiversidgeandCund
y,1995).
Nanoparticlesaretypicallyproducedbywetmilling,homogenization,orprecipitationte
chniques(LiversidgeandCundy,1995;MeriskoLiversidgeetal.,2003;DouroumisandFahr,2007).
Nanosuspensionisthermodynamicallyunstable,beingpronetoparticleregrowthandhencesurface
stabilizersareusedtomaintainparticlesize.Thechoiceandconcentrationofstabilizers
areselected
topromotetheparticlesizereductionprocessandgeneratephysicallystableformulatio
ns.Tobe
effective,thestabilizermustbecapableofwettingthesurfaceofdrugsubstanceandpro
vidinga
stericorionicbarriertopreventthenanoparticlefromaggregation.Manycommonlyuse
dphar-

maceuticalexcipientssuchasthecelluloses,pluronics,polysorbates,andpovidonesar
eacceptable
stabilizersforgeneratingphysicallystablenanoparticledispersions(LiversidgeandCu
ndy,1995).
Cellulosesincreaseaqueousviscosityandretardsedimentationofsuspendeddrug,the
rebyimprovingdoseuniformity.Commonformulationincludesvehiclescontainingdispersionagen
tssuchas
hydroxylpropylcelluloseintherangeof1
3%andsurfactantssuchasDocusateSodium(DOSS)in
therangeof0.11%.
Nanosuspensionhasfoundwideuseinrecentyearsfororal,injectable,inhalation,andin
trademeralapplications(MeriskoLiversidgeetal.,2003).Thenanosuspensiontechnologyisoftremendous
helpforpoorlywatersolubledrugsforconductingvariousscreeningstudiesatthepreclinicalstage.
Astheformulationdoesnotcontainanymajorcosolvent,resultsofsuchstudiescanbem
orepreciselycorrelatedwiththecandidatemolecule.Themethodhasmanyformulationandth
erapeutic
advantages,suchasasimplemethodofpreparation,lessrequirementofformulationex
cipients,
reductioninthetoxicityofthecandidatedrug,signi-cantincreaseinthebioavailabilityle
adingto
decreaseintheoptimaldose,decreasedfedfastedvariability,andsoforth(Rabinow,2004;Wuetal.,
2004;Dubey,2006).Oneofthemainapplicationsofnanosuspensionhasbeentheformu
lationof
pharmaceuticalcompositionsthatcanbeadministeredintravenously.Forintravenous
administration
ofasuspension,theparticlesinthesuspensionneedtobelessthan5
m,whichisthediameter
ofthesmallestbloodcapillariesinthebody.Intravenousadministrationofthenanosusp
ensionmay

resultinadvantagessuchasnohigherconcentrationoftoxiccosolventsandimprovedth
erapeutic
effectofthedrugavailableasaconventionaloralformulation.Nevertheless,severalpro
ductsare
nowavailablebasedonnanosuspensionprinciples.
Thenanosuspensiontechniqueusuallydoesnotworkwellforbasiccompoundswithhigh
pHdependentsolubility.Whenadministeredorally,nanoparticlesofabasicdrugmaydissol
verapidly
instomach,butonlytoprecipitateoutinthesmallintestineasuncontrolledparticles,thu
sdefeating
thepurposeofnanosizing(Peagrametal.,2005).Sometendtoagglomerateorincreasei
nparticle
sizeowingtocrystalgrowth(Neervannan,2006).Anotherdisadvantageisthatnotallco
mpounds
canformnanosuspensions.

Therearenumerousexampleswheresizereductiontechniqueshavebeenappliedtopo
orlywatersolublecompoundsinordertoincreasetheirdissolutionrateandimprovebioavailability
following
oraladministration(Levyetal.,1963;HintzandJohnson,1989;Chaumeil,1998;Rasena
ckand
Muller,2002;Kayseretal.,2003;Kocbeketal.,2006;Pouton,2006).Sizereduction,parti
cularly
atthesubmicrondimension,representsavaluablemeansofimprovingoralabsorptiono
fpoorly
watersolublecompounds.AsshowninFigure17.10,theincreaseindissolutionratefromsolid(
x)
withsizereductionprovidesmoredruginsolution(x)availableforabsorptionduringgast
rointestinaltransit.Therefore,thefractionofunabsorbeddrugdecreasesasoverallbioavailabili
tyincreases.

Nanoparticlesinparticularprovideforalargesurfaceareaavailablefordissolutionsince
sizesare
generally<1000nmindiameterand invivo
agglomerationisminimizedbyparticlestabilization.
Table17.2illustratestheabsoluteoralbioavailabilityofseveralDanazolformulations:n
anoparticle
dispersion,solubilizedcyclodextrinoralformulation,andconventionalsuspension.Da
nazolrepresentsapoorlywater-solublecompound(10
g/mL)whoseoralbioavailabilityisdissolutionlimited.
TheresultsindicatedthatsizereductionofDanazolcrystalsfrom10
masconventionalsuspension
tosizeslessthan200nmnanoparticledispersionresultedinapproximatelya16foldincreasein
absolutebioavailability(LiversidgeandCundy,1995).Studieswithanoralphenytoinna
noparticle
dispersionindicatedincreasesinabsorptionofnearlythreefoldwhenadministeredtohe
althyvolunteersascomparedtoanaqueoussuspensionofmicronizeddrugsubstance(Woodetal.,
1995).For
theanti-inammatoryagent,naproxen,ithasbeendemonstratedintheratthatsizereductionof
naproxenfrom2030
mto270nmledtoresultsindicatingdecreasedgastricirritationfollowing
oraladministrationaswellasafourfoldincreaseintherateofabsorption(Liversidgeand
Conzentino,
1995).Furthermore,inhumanclinicaltrials,thetimetoonsetofactionofananoparticleor
alsuspensionofnaproxenreachedsigni-cantplasmalevels( t90)inlessthan20min,whichwa
s12-fold
fasterthancommercialformulationsoflargerparticlesize(Figure17.11).

Bodmeier, R., 2008, Polymeric Dispersions as Drug Carriers, Freie

Universitt Berlin, Berlin, Germany.
Nanopartikel adalah partikel koloidal dengan ukuran lebih kecil dari 1 mm. Zat
aktif dapat berada pada beberapa kondisi, yaitu larut dalam matriks polimer,

terenkapsulasi, teradsorbsi atau menempel pada permukaan pembawa koloid.

Syarat nanopartikel meliputi nanocapsules dan nanospheres. Nanokapsul
memiliki struktur berupa selaput inti (sistem reservoir), sedangkan nanospheres
berupa sistem matriks.

Rowe, RC., et al, 2009, Handbook of Pharmaseutical Excipients, Sixth

Edition, Pharmaseutical Press, London.
1. kitosan
Partialdeacetylationofchitinresultsintheproductionofchitosan,
whichisapolysaccharidecomprisingcopolymersofglucosamine
and N-acetylglucosamine.
Chitosan is used in cosmetics and is under investigation for use in a
number of pharmaceutical formulations. The suitability and
performance of chitosan as a component of pharmaceutical for
mulations for drug delivery applications has been in vestigated in
numerous studies. These include controlled drug delivery applications,
use as a component of mucoadhesive dosage forms, rapid release
dosage forms, improved peptide delivery, colonic drug delivery
systems, and use for gene delivery. Chitosan is a cationic polyamine
with a high charge density at pH < 6.5, and so adheres to negatively
charged surfaces and chelates Metal ions. It is a linear polyelectrolyte
with reactive hydroxyl and amino groups (available for chemical
reaction and salt formation). The properties of chitosan relate to its
polyelectrolyte and Polymeric carbohydrate character. The presence of
a number of Amino groups allows chitosan to react chemically with
anionic systems, which results in alteration of physicochemical
characteristics of such combinations. The nitrogen in chitosan is mostly
in the form of primary aliphatic amino groups. Chitosan there for
undergoes reactions typical of amines: for example, N-acylation and
Schiff reactions. Almost all functional properties of chitosan depend on
the chain length, charge density, and charge distribution. Numerous
studies have demonstrated that the salt form, molecular weight, and

degree of deacetylation as well as pH at which the chitosan is used all

influence how this polymer is utilized in pharmaceutical applications.
2. Na Alginat
Natrium alginat utamanya terdiri atas garam natrium dari asam alginat,
yang berupa campuran asam poliuronat yang tersusun atas residu asam
D-mannuronat dan L-asamguluronat. Kini natrium alginat telah
digunakan untuk mikroenkapsulasi obat, yang berbeda dengan teknik
mikroenkapsulasi konvensional lainnya yang menggunakan sistem
pelarut organik. Natrium alginat juga telah digunakan untuk
pembentukan nanopartikel (Rowe et al, 2009).
Pathak, Y., and Deepak, T., 2009, Drug delivery nanoparticles
formulation and characterization, Informa Health careUSA, Inc., New
York.
Model nanopartikel penghantaran obat menggunakan polimer biodegradabel
memperlihatkan suatu pendekatan yang menjanjikan untuk meningkatkan
bioavailabilitas obat dengan kemungkinan penguarangan dosis efektif, sehingga
mengurangi kemungkinan potensi toksisitas dan efek samping obat,
menghantarkan obat ke jaringan spesifik dan mengefektifkan stabilitas obat
dalam matriks polimer; melindungi dari enzim danmekanisme pertahanan
normal tubuh lainnya. Disamping nanopartikel (Pathak and Deepak, 2009).