Processing and Scale-up of Polymeric Nanoparticles - Intracellular Delivery: Fundamentals and Applications - page 447

or tangential filtration methods (Limayem et al. 2004 ). Concentration of
nanoparticle dispersion based on dialysis is a gentle method in which the water
from the nanoparticle dispersion is removed thanks to the application of an
osmotic pressure on the dialysing bag using a solution of high molecular weight
polymer as counter dialysing medium. The dispersions can be concentrated up to
factors of 50 without producing aggregation of the nanoparticles and in a couple
of hours (Vauthier et al. 2008 ).
Nanoparticle dispersions for parenteral administration need to be sterilized.
Autoclaving is not always suitable because nanoparticles may be modified and drug
may loose their activity (Rollot et al. 1986 ; Masson et al. 1997 ; Boess et al. 1996 ).
Autoclaving can be used to sterilize nanoparticles made of chitosan-carboxymethyl
dextran polyelectrolyte complexes (Lin et al. 2009 ). Gamma irradiations also need
to be applied with caution because it can significantly modify the characteristics of
the polymer composing the nanoparticles and the drug hence the initial perfor-
mance of the drug delivery system (Sintzel et al. 1997 ; Masson et al. 1997 ;
Athanasiou et al. 1996 ). However, this technique was found suitable to sterilize
doxorubicin-loaded poly(butyl cyanoacrylate) (PBCA) nanoparticles (Maksimenko
et al. 2008 ) and vaccine nanoparticles made of poly(anhydride) and containing
Brucella ovis antigen (Da Costa Martinez et al. 2009 ). Both types of nanoparticles
showed an excellent stability to irradiation without radiolysis of the polymer and
with good performance preserving the integrity of the drug/antigen activity.
Sterilization by filtration can be applied only on nanoparticle dispersions with a
diameter below 0.22 mm which is a major limitation (Memisoglu-Bilensoy and
Hincal 2006 ). High Hydrostatic Pressure treatment (HHP) proved its efficacy to
destroy vegetative forms of microorganisms found in nanoparticle dispersions
(Brigger et al. 2003 ). However, this technique still needs improvement to make
possible elimination of bacteria spores before if can be validated as a suitable
method of sterilization for nanoparticles. It could be interesting to also explore
other sterilization methods such as those based on the use of gaz plasma and ethyl-
ene oxide which were recently applied on gold nanoparticles developed for bio-
medical applications (França et al. 2010 ). In the absence of suitable satisfactory
method of sterilization, preparations must be done in sterile environment which
complicates the development for clinical applications.
As valuable for many pharmaceutical products, storage of nanoparticle drug
delivery systems under a dried form would be the preferred method. In general,
nanoparticles are obtained in a liquid medium after preparation. Transformation of
the liquid dispersion into a dried powder can be achieved either by lyophilisation
(Nemati et al. 1992 ; De Chasteigner et al. 1996 ; De Jaeghere et al. 1999 ;
Abdelwahed et al. 2006 ) or spray-drying (Tewa-Tagne et al. 2007 ) which are both
suitable at industrial scale. Considering freeze drying, it may be required to add
cryoprotectants to the nanoparticle dispersion to prevent aggregation of nanoparti-
cles during the reconstitution of the dispersion from the dried powder prior to use.
Optimization of the freeze drying cycle improves the quality of the freeze dried
product (Patapoff and Overcashier 2002 ; Abdelwahed et al. 2006 ). In contrast with
freeze drying, spray drying is a continuous process. Other advantages are the low