Lessons Learned from Pharmaceutical Nanomaterials - Safety of Nanomaterials along Their Lifecycle - page 114

do not permeate the intact stratum corneum to reach the blood circulation or
the lymph (Labouta et al. 2011; Labouta and Schneider 2013). However, serious
damage like strong sun burn might alter the penetration into the skin (Monteiro-
Riviere et al. 2011). For the purpose of drug delivery, most nanopharmaceuticals
are designed to stay either at the surface (in the formulation matrix) or penetrate
into the epidermis (depending on their hydrophobicity and the dispersing vehicle)
to act as a depot system. The toxicological risk for such systems is comparatively
low and controllable. The hair follicles were reported to act as a depot reservoir
enabling a prolonged residence time for particles in the suitable sub-micrometer
size range (Lademann et al. 2007). Some recent work aims to make use of this as
needle-free, noninvasive vaccination route (Mittal et al. 2013; Mittal, Raber, and
Hansen 2013).
Nanoparticles are moreover of special interest for the delivery of active phar-
maceutical ingredients to the brain. They have the ability to enhance the transport
across the blood-brain barrier (formed by the endothelium of the blood vessels) for
actives, which are nonpermeable in their free form. Special carrier surface proper-
ties (negative charge and polysorbate 80 coating, and specific targeting ligands) are
reported to be helpful (Wohlfart, Gelperina, and Kreuter 2012). Deposition of insolu-
ble particles in the brain is a scenario linked with the suspicion of neurodegenerative
disease generation, which could be caused by reactive oxygen species or inflam-
mation (Bondy 2011). The formulation of colloids used in the brain may therefore
be critical. Perlstein evaluated dextran-coated colloids by measuring the clearance
after transcranial injection or infusion. In these studies, maghemite nanoparticles
had a slow clearance of 80%-90% from rat brain with some particles remaining in
the brain cells (Perlstein et al. 2008). Another study evaluated dextran-stabilized
superparamagnetic iron oxide particles and found a 90% clearance after 3 months
(Polikarpov et al. 2013).
6.3 GET TO KNOW YOUR NANOPARTICLES
When speaking about pharmaceutical products in general, it is always required to
prove not only their efficacy but also their safe use and to ensure quality. Therefore,
it is a matter of course that nanopharmaceuticals are tested for their safety before
entering clinical trials and eventually the market situation later on. The established
methods for efficacy and safety testing were developed for small molecule actives
and their formulations and are not always easy to convert to nanopharmaceuticals.
The higher complexity of nanopharmaceuticals can cause variance in their spatial
distribution, their chemical or physical appearance, interaction, and so on. The safety
evaluation gets more demanding as the particle architecture can change according
to the (biological) environment and thereby causing various types of interactions
(protein binding, cellular recognition, and cellular uptake). The efficacy and safety
can vary because of changed absorption, distribution, metabolism, and excretion
(ADME) properties or altered drug release speed. The special problem here with
nanopharmaceuticals is the difficulty to analyze small variances in the particles
architecture at the nanoscale. For this reason let us have a short look at the available
methods for nanoparticle characterization.