Lessons Learned from Pharmaceutical Nanomaterials - Safety of Nanomaterials along Their Lifecycle - page 112

nanoparticles into four major safety classes (Keck and Muller 2013). The NCS may
serve as a good starting point for discussion of nanopharmaceutical formulations
and can be even of interest for nonpharmaceutical nanoparticles risk assessment.
It is based in the first line on size and biodegradability and in the second line on
biocompatibility of nanoparticles. They are categorized into four classes of increas-
ing risk, due to size and persistency: Class 1 particles have a size above 100 nm and
are biodegradable, whereas particles in class 2 are not biodegradable. Both classes
show no endocytosis of particles. In classes 3 and 4, particle size is below 100 nm
and particles show endocytosis. To differ between classes 3 and 4, particles in class 3
are biodegradable, whereas particles in class 4 are not. This new NCS helps to con-
sider most relevant properties of nanoparticles related to their potential nanotoxicity.
Other properties, such as solubility behavior, number and frequency of application,
and medical indication, could be helpful in risk assessment. It is obvious that a single
application treatment can easily tolerate low biodegradation than a repeated dosed
therapy. In the development of an antibiotic carrier system with short-term dosing
and a wanted immune system response, a mild activation of the immune system
might even be helpful, while the same reaction might not be tolerable when develop-
ing nanopharmaceuticals for an anti-inflammatory therapy.
Besides the active pharmaceutical ingredient (API), there are also excipients in
each formulation, which have to be considered often as at least partly active ingre-
dients also since they functionally contribute to the drug effect and are not inert
carriers. Therefore, materials and substances that already have a pharmaceutical
acceptance are preferred. These materials should be of high purity, biocompatible,
biodegradable, and nontoxic, to get a valid estimation of the safety profile of the final
formulation. If not already used in some FDA (US Food and Drug Administration)-
approved products, materials for drug product formulation have generally GRAS
status (Generally Recognized As Safe). This status, however, depends on the applica-
tion route in terms of the impact on biodistribution and biokinetics of the particles.
6.2 EFFECT OF THE ROUTE OF APPLICATION: CHANCES
AND RISKS OF NANOPHARMACEUTICALS
The application route guides biodistribution, particle elimination, and thus efficacy
of nanopharmaceuticals. The principal decision has to be taken if a systemic therapy
or a local therapy better suits within the therapeutic concept of the target disease.
Until now the dominating route for nanopharmaceuticals is the intravenous (iv)
route of application. One advantage is the certainty of the dose reaching the circu-
lation, since the need to overcome an epithelial barrier is not given. In particular,
in cancer therapy the iv administration plays an important role, as nanoparticles
are able to accumulate at least to some extent in a tumor tissue, due to the enhanced
permeation and retention (EPR) effect. Disadvantages of the iv route are the poten-
tial unwanted accumulation in nontarget tissues or organs. For example, particles
of larger sizes or nanoparticles with some aggregation tendency can accumulate in
the fine capillaries of the lungs. Particles with hydrophobic or highly charged sur-
faces are prone to opsonization with blood proteins and thereby enhanced uptake
and elimination by macrophages (Aggarwal et al. 2009). Consequently, special