Lessons Learned from Pharmaceutical Nanomaterials - Safety of Nanomaterials along Their Lifecycle - page 113

surface designs have to be realized to prolong the residence time in the blood
circulation. For enhanced patient compliance the oral route is most interesting
for drug delivery. The pH differences, the mucus layer, the enzymatic environ-
ment, food effect, and so on make the gastrointestinal tract a real challenge for
nanopharmaceuticals. The protection of nanopharmaceuticals from the hostile pH
in the stomach is difficult as this means either a conversion into some solid dos-
age form first (often causing aggregation) or coating the nanoparticles directly
with a protective layer (complete coating needed, which is difficult to achieve).
The mucus barrier is easier to cross for small molecule drugs than for particulate
carriers, as they face more difficulties in diffusion through the mucin mesh. The
high turnover rate of the mucus layer and the uppermost epithelial cells, however,
help in efficient nanoparticle elimination. Only for some nanoparticles with spe-
cial properties a low level of absorption has been reported, achieving access to the
circulation (Landsiedel et al. 2012). Nevertheless, some therapeutically interest-
ing nanopharmaceutical formulations could use the pathophysiologic changes in
inflammation for prolonged particle retention (Collnot, Ali, and Lehr 2012) or the
uptake via M-cells for vaccination (Slutter et al. 2009).
The lungs are an interesting epithelial barrier since it is constructed as thin as
possible for efficient gas exchange and is less equipped with degrading enzymes
when compared to the gastrointestinal tract. In order to deliver drugs either directly
to the lung tissue or without much enzymatic or metabolic loss into the circulation
the pulmonary route is mostly attractive. Designing particles in the correct size range
and shape for sufficient aerodynamic properties enables the avoidance of mucocili-
ary clearance and a deposition in the alveolar region. That this concept works for
protein delivery could be proven with Exubera ® , the inhalable insulin marketed by
Pfizer (Skyler et al. 2007). The reason for the market withdrawal of Exubera was
low acceptance and high cost (Bailey and Barnett 2007). From a risk assessment
point of view, however, particles deposited in the deep lungs are more difficult to
remove. The clearance of particles from the alveoli occurs in first line by alveolar
macrophages, while under conditions of infection neutrophiles are recruited to assist
in pathogen clearance (Hasenberg, Stegemann-Koniszewski, and Gunzer 2013). The
macrophage clearance is faster for microparticles than for nanoparticles (Todoroff
and Vanbever 2011). Particles that cannot be completely phagocytosed by macro-
phages are a safety risk, as we should have learned from asbestos. Particles that are
causing immune stimulation, in particular if they are more persistent, may also be
considered as health risk as the immune mediators can damage the lungs or other tis-
sues (Geiser and Kreyling 2010). As a consequence, only a few excipients are known,
which are considered safe enough for drug delivery to the lungs, and so far all of
them are water soluble. Particles made from water soluble materials without cross-
linking simply dissolve after landing. They are not suitable to deliver drugs, which
need carriers for intracellular delivery (e.g., intracellular active peptides and nucleic
acid drugs). An approach to combine the higher efficacy of alveolar deposition of
microparticles with the slower clearance by alveolar macrophages of nanoparticles
is to form microparticles from nanoparticles (Tsapis et al. 2002).
The skin with its multilayered epidermis is a very tight barrier, which prevents
unintentional permeation. There is quite a good agreement that nanoparticles