Biomedical Engineering Reference
In-Depth Information
(Schöler et al.
2000
) and in vivo (Schöler et al.
2001
). Recently toxicity investigations
were published on the new phospholipase A
2
inhibitors PX-13 and PX-18 nano-
crystals (Pardeike and Müller
2010
). The nanocrystals were invesitgated using the
EPISKIN Test and the HET-CAM test to study the eye irritation potential. The
nanosuspensions were found to be dermally safe, they were not or only slightly
irritant to the eye.
It was also found that nanocrystals can even reduce irritancy to cell layers, e.g. the
gastric wall. Nanocrystals of naproxen were shown to decrease the gastric irritancy
(Liversidge and Conzentino
1995
) compared to the drug powder. Intraperitoneally
injected azodicarbonamide (ADA) was not irritant as nanosuspension, much
better tolerated than irritant micrometer crystals (unpublished data). The underlying
mechanism could be that the drug is more evenly, finely distributed about the
walls of the gut or the peritoneum, similar to the improved tolerability of pellets
compared to tablets loaded with irritating drugs. In addition, size and form of the
drug crystals might also affect the tolerability (e.g. long needles compared to small
cubes, e.g. similar to the toxicity of needle-like carbon nanotubes).
As a general aspect, nanocrystals normally change the pharmacokinetic profile of
actives (i.e. higher c
max
, shorter t
max
). This can lead locally to a higher drug exposure
of cells (e.g. kidney at higher plasma concentrations). This effect is well described
for the nephrotoxicity of Amphotericin B. The nephrotoxicity is higher in formu-
lations leading to higher concentrations of free Amphotericin B in the blood
(Amphotericin B injectable solution versus Ambisome
®
liposomes). Definitely,
there is a need for further closer examination of cellular effects of nanocrystals.
6
Nanocrystal Products on the Market - “Cellular
Delivery Mechanism I”
6.1
Cosmetic/Dermal Market
Normally the cosmetic market watches carefully developments in pharmaceutical
labs and industry to identify technologies and carrier systems with potential use in
cosmetics. The classical example are the liposomes which appeared first on the
cosmetic market (1986, product Capture by Dior) before entering the pharmaceutical
market around 1990. In case of the nanocrystals this was different. The nanocrystals
appeared first on the pharmaceutical market in 2000 (product RAPAMUNE
®
company Wyeth). The potential of nanocrystals for dermal delivery was realized a
few years later (Petersen
2006
). The first products were placed on the market in
2007 (line Juvedical, company Juvena).
In these products the delivery of the cosmetic active is not achieved by intracel-
lular uptake of the nanocrystals. Based on the physical properties of the nanocrystals,
they deliver molecules to the cell which dissolve from their surface, which we call
delivery mechanism I. In delivery mechanism II, delivery of active to the cell takes
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