Biomedical Engineering Reference
In-Depth Information
particles. tend. to. show. enhanced. saturation. solubility. compared. to. crystals. (Thies. and.
Müller.1998;.Violante.and.Fischer.1991)..The.precipitation.approach.is.one.of.the.bottom-up.
techniques,.which.are.simple.and.cost-effective.as.well.as.relatively.easy.to.scale-up,.but.
fundamentally.dificult.to.maintain.and.stabilize.the.particle.size.(Keck.and.Muller.2006).
As. an. alternative. of. the. bottom-up. system,. milling. techniques. were. used. as. a. top-
down.system..The.milling.techniques.include.the.pearl/ball.milling.technique.and.the.
high. pressure. homogenization. technique.. A. pearl. milling. system. is. the. basis. of. the.
nanocrystal.technique.developed.by.Liversidge.and.coworkers.(Suman.et.al..2009)..At.
irst,.macrosuspension,.where.the.drug.is.dispersed.to.random.sizes,.is.added.inside.of.a.
container..The.container,.which.has.milling.pearls.and.dispersed.drug,.starts.to.ground.
the. drug. by. moving. the. pearl.. Rapamune. and. Emend. were. the. initial. products. made.
from.this.method..Even.though.this.technology.brings.patients.increased.compliance,.
the.milling.process.seems.to.have.some.dificulties..In.case.of.a.physically.hard.drug,.
it. needs. much. more. time. to. be. ground. compared. to. a. relatively. less. hard. drug.. Also,.
there. is. potential. contamination. of. milling. material. eroded. from. the. pearl. (Keck.
and. Muller. 2006).. In. contrast. to. the. milling. process,. high-pressure. homogenization.
systems. employ. two. kinds. of. techniques,. which. are. microluidization. technology.
(IDD-P™,. SkyePharma. Canada. Inc.). and. piston-gap. homogenization. technology.. The.
microluidization.technique.generates.nanocrystals.by.collision.of.two.luid.streams.at.
high.pressure,.which.pass.through.collision.chambers.of.two.different.shapes,.Y-.and.
Z-shapes.. It. requires. 50-100. cycles. to. generate. nanocrystals. small. in. size. suficient.
for. increasing. the. solubility. (Keck. and. Muller. 2006).. The. piston-gap. homogenization.
technology.includes.two.major.techniques,.which.are.DissoCubes
®
.(SkyePharma.PLC).
and.Nanopure
®
.(PharmaSol.GmbH)..In.the.DissoCubes.technology,.a.drug.suspension.
is. placed. inside. of. a. container. whose. diameter. is. around. 3.cm,. then. passes. through.
the. very. narrow. homogenization. gap. (3-15.μm). under. the. pressure. of. 150-1500. bar. to.
generate.considerably.high.velocity.(Müller.et.al..1999)..While.the.DissoCubes.technology.
uses. pure. water,. Nanopure. technology. produces. nanocrystals. in. nonaqueous. media.
such. as. polyethylene. glycol. (PEG). or. oils.. Recently,. combinations. of. precipitation. and.
homogenization. have. been. developed. (e.g.,. Nanoedge
®
,. Baxter).. At. present,. there. are.
several.nanocrystal.formulations.under.development,.such.as.Semapimod
®
,.PAXCEED™,.
and.Theralux™.
23.2.2
.
Liposomes and Niosomes
Many.types.of.nanoliposomes.have.been.used.clinically,.such.as.liposomal.amphotericin.
B. to. cure. invasive. fungal. infections. since. 1995,. daunorubicin. citrate. liposomes. to. treat.
Kaposi's. sarcoma. since. 1996,. and.sustained. release. of. cytarabine. liposomes.for.lympho-
matous.meningitis.since.1999.(Bawa.2008)..Liposomes.can.encapsulate.hydrophilic.drugs.
in.the.aqueous.core.and.embed.lipophilic.drug.between.lipid.bilayers..Liposomes.in.the.
size.range.of.50-250.nm.are.usually.made.as.unilamellar,.while.those.larger.than.500.nm.
are.multilamellar..A.unilamellar.liposome.is.preferred.to.encapsulate.hydrophilic.drugs.
because.of.a.large.portion.of.aqueous.core..On.the.other.hand,.multilamellar.vesicles.may.
be.useful.for.incorporating.lipophilic.drugs.due.to.its.higher.portion.of.the.lipid.structure.
(Fang.et.al..2006;.Mufamadi.et.al..2011;.Zucker.et.al..2009).
Liposomes.are.usually.prepared.by.ilm.hydration,.organic.solvent.injection,.or.reverse-
phase. evaporation.. Of. these,. the. ilm. hydration. method. is. frequently. used. to. make.
liposomes.. Recently,. the. application. of. liposomes. has. progressed. from. conventional.
nanoliposomes. to. stealth. nanoliposomes.. These. stealth. liposomes. can. be. fabricated.
