Processing and Scale-up of Polymeric Nanoparticles - Intracellular Delivery: Fundamentals and Applications - page 443

In contrast with the previous methods, nanoparticles form within milliseconds
(Moinard-Chécot et al. 2008 ). The so called emulsification-inverse salting out
method is a specific case of preparation of nanoparticles based on solvent extrac-
tion. The emulsion is prepared with a solution of polymer dissolved in acetone
which is dispersed in a concentrated aqueous solution of electrolytes or mono/
disaccharides. After simple dilution of the emulsion with an excess of water, the
electrolyte or saccharide concentration in solute dropped down inducing instanta-
neous diffusion of acetone out of the emulsion droplets towards the continuous
phase of the emulsion. As a consequence, the polymer precipitates as nanoparticles
(Allémann et al. 1992 ; Ibrahim et al. 1992 ).
Alternative methods to polymer precipitation are based on gelation of polymers
contained in the emulsion droplets of water-in-oil emulsions. Suitable polymers
used to prepare nanoparticles by this method are polysaccharides. For instance,
agarose nanoparticles are obtained by decreasing the temperature of the emulsion
prepared at high temperature allowing the polysaccharide to solubilise (Wang and
Wu 1997 ). Pectine nanoparticles are prepared from two emulsions, one containing
the polysaccharide and the second a basic aqueous dispersed phase. By mixing the
two emulsions together, gelation of pectine contained in the emulsion droplets of
the first emulsion is promoted thanks to an increase of pH of the emulsion droplets.
This gelation produces the nanospheres (Tokumitsu et al. 1998 ).

3 Pilot Scale Production of Nanoparticles

Only few articles report preparation of large amount of nanoparticles for drug
delivery applications. Indeed, nothing is known about transposition from labora-
tory preparation to production of clinical batches for doxorubicin loaded
poly(alkylcyanoacrylate) nanoparticles, Transdrug ® , used in phase II/III clinical trials
(BioAlliance Pharma 2010 ). No more is known about the production of a marketed
formulation of paclitaxel-loaded albumin nanoparticles, nab-paclitaxel or Abraxane ® ,
used in clinics in the USA for the treatment of metastatic breast cancer (Hawkin et al.
2008 ; Petrelli et al. 2010 ). The most detailed data about the scale up of production of
pharmaceutical grade nanoparticle dispersions are only available on the pilot scale
production of nanoparticles prepared by the emulsification-solvent diffusion method
and by the nanoprecipitation method. By extension, the scale up approach developed
for the method of emulsification-solvent diffusion was also applied to produce large
batches of nanoparticles by the emulsification-reverse salting out method. As a
reminder, a pilot-scale production is intermediate between the laboratory and the
industrial scale production. Pilot size production is aimed to simulate the closest as
possible industrial production and hence needs to integrate all parameters that need
to be optimized before reaching the industrial production. This topic was recently
extensively reviewed by the authors (Vauthier and Bouchemal 2009 ).