Processing and Scale-up of Polymeric Nanoparticles - Intracellular Delivery: Fundamentals and Applications - page 437

Joralemon et al. 2010 ). The two major methods of preparation of drug loaded
polymer micelles are based either on nanoprecipitation or on dialysis. The polymer
micelles are to be produced in a continuous aqueous phase. In general, the solubil-
ity of the amphiphilic polymer is higher in organic solvents compared to water. The
use of an organic solvent miscible with water promotes the dissolution of unimers
of the polymer helping the formation of well structured polymer micelles when
solubility conditions change by addition of large amount of water such as in the
nanoprecipitation method (Johnson and Prud'homme 2003 ; Forrest et al. 2008 ) or
by the progressive replacement of the organic solvent by water through a dialysis
against water (Kim et al. 1999 ; Lee et al. 2003 ; Huh et al. 2005 ; Park et al 2005 ).
Eventually, the polymer solution is slightly diluted by the addition of a limited
amount of water prior to dialyse against water (Jie et al. 2005 ; He et al. 2007 ; Kang
and Leroux 2004 ). Typical organic solvents are chosen among acetonitrile (ACN),
tetrahydrofuran (THF), dimethylformamide (DMF), or N-N-dimethylacetamide
(DMAc). The drug to be encapsulated in the polymer micelles is added in the poly-
mer solution before induction of the micelle formation achieved by modifications
of polymer solubility conditions.

2.1.2 Obtaining Nanoparticles Through Controlled Gelation

Gels are a three-dimensional polymer network swollen by solvent. Several poly-
mers form gels either by cooling down a solution prepared at hot temperature or
by adding small molecules which crosslink polymer chains through chemical
linkage or by physical interactions. Obtaining nanoparticles from a polymer
solution through a gelation process was described inducing gel formation by
physical interactions. Typical polymers are charged polysaccharides dissolved at
a low concentration in an aqueous solvent. The addition of a small molecule
bearing a low number of opposite charges induces formation of gel nanoparticles
through ionic gelation. This can easily be followed by measuring the viscosity
of the polysaccharide solution which dropped down when the nanoparticles
formed, by electron microscopy and by light scattering allowing to measure the
size of the nanoparticles formed (Vauthier et al. 1994 ; Vauthier and Couvreur
2000 ). In general, the nanosized gels form at low concentrations of both polymer
and gelling agent.
This method was applied with alginate which gelify with calcium ions.
Consolidation of nanogels formed with calcium can be achieved by addition of a
positively charged polyelectrolyte. Poly-lysine was used in the earlier development
but most of the recent works are considering chitosan as another suitable polyelec-
trolyte candidate (Rajaonarivony et al. 1993 ; Vauthier and Couvreur 2000 ; Douglas
and Tabrizian 2005 ). Alginate nanoparticles produced by controlled gelation can
easily be loaded with oligonucleotides. They protect oligonucleotides from degra-
dation by nucleases (Aynié et al. 1999 ). This system was also highly investigated
for the delivery of oral formulation of peptides including insulin (Li et al. 2007 ;
Sarmento et al. 2007 ). Chitosan based nanoparticles can be obtained by gelation