Biomedical Engineering Reference
In-Depth Information
viscous suspensions are more difficult to process. Therefore at the end of the day
it might be faster to have longer milling time but using a less concentrated, less
viscous suspension.
5
Nanotoxicity and Regulatory Aspects
A key issue in nanocarrier development since decades is the regulatory status of
the excipients used. In addition, in recent years potential nanotoxicty is coming
increasingly into the focus of the consumer, triggered by often uncritical, simplifying
reports in the popular press. Nanotoxocity is sincerely an issue, because by transfer-
ring material to the nanodimension its physico-chemical properties and subsequently
its interaction with the biological environment, mainly the cells, change.
Many nanocarriers originating from the lab are made from materials which are
not accepted for use by the authorities, e.g. newly synthesized polymers to give the
nanoparticles a special performance. Industry is very reluctant to invest in expensive
toxicity studies, especially when the result is questionable with a new compound,
thus hindering these nanocarriers to enter clinical trials and the market. The situation
is not that much different, when excipients are used which are accepted by authorities,
but not accepted for the respective purpose. The classical example is the poly lactic
glycolic acid polymer (PLG). They are on the pharmaceutical market as micropar-
ticles for injection (e.g. Enantone Depot, Decapeptyl Depot). However, when making
small particles from this polymer, pronounced cytotoxicty was found in macrophage
cultures (Smith and Hunneyball
1986
). In contrast to 50-100 mm microparticles,
particles with a size of a few mm and nanoparticles can be taken up by macrophages.
Intracellular degradation leads to release of lactic and glycolic acids, causing at
too high concentration the observed cytotoxicity - despite being both physiological
compounds in the body.
In contrast to many other nanocarriers, the drug nanocrystals can be made from
regulatorily accepted excipients only. They consist just of the drug and stabilizers.
One can choose from a broad range of stabilizers regulatorily accepted in formulations
for the respective administration route (dermal, oral, intravenous (i.v.), intramuscular,
etc.). Examples range from various polymers for oral administration (e.g. polyvinyl
alcohol (PVA), polyvinyl pyrrolidon (PVP)) including the basically membrane-toxic
sodium dodecyl sulphate (SDS) to i.v. accepted lecithins, Tween 80, Poloxamer
188, low molecular weight PVP. This gives a big advantage to this delivery system
regarding use in the clinic and entering the market. Of course, the question of
potential nanotoxicity still needs to be discussed.
According to the nanotoxicological classification system (NCS, Fig.
3
) different
levels of tolerability and toxicity are distinguished, based on the particles size and
the degree of biodegradability. There are two size classes of the NCS, nanoparticles
in the range of about 100-1,000 nm can only be taken up by macrophages, possess
therefore only access to a limited number of body cells, having therefore a lower
toxicological risk. Nanoparticles below 100 nm can enter any cell of the body by
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