Nanocrystals: Production, Cellular Drug Delivery, Current and Future Products - Intracellular Delivery: Fundamentals and Applications - page 427

7 Targeted Nanocrystals in Development - “Cellular

Delivery Mechanism II”

In these developments the nanocrystals deliver the drug to the cells by internalization.
The nanocrystals are taken up, and dissolve inside the cell (= cell delivery mecha-
nism II). The administration route used by now is intravenous injection in form
of aqueous nanosuspensions. These nanosuspensions need to be made isotonic by
addition of glycerol. Addition of NaCl has to be avoided, because this reduces the
zeta potential of the nanocrystals and causes subsequently aggregation. Furthermore
the nanosuspensions need to be sterile, either made sterile by terminal sterilization
or be produced aseptically.
At the beginning i.v. nanosuspensions were developed with the aim to replace
toxicologically problematic excipients in existing i.v. formulations on the market.
Examples are Taxol and Sporanox. Taxol contains paclitaxel solubilised with
Cremophor EL causing sometimes anaphylactic shocks during administration
(Strachan 1981 ; Dye and Watkins 1980 ). Sporanox contains itraconazol made
soluble by inclusion into hydroxypropyl cyclodextrin (HP-CD). The HP-CD can
cause nephrotoxicity (Szejtli 1988 ). The technological aim was to produce nano-
suspensions of both drugs, whereas the nanocrystals are stabilized by well tolerated
stabilizers, e.g. lecithins or Poloxamer 188.
Paclitaxel nanosuspensions could be successfully produced, nanocrystal size
about 300 nm. Stabilizers used were well tolerable phospholipon 90 and various
Poloxamers (Böhm 1999 ; Böhm et al. 1997 ). However after i.v. administration of
the nanosuspension the pharmacokinetic was completely different to the solution
Taxol. The drug nanocrystals were recognized as being foreign to the body and
taken up the macrophages of liver and spleen. The same was observed for an
injected itraconazole nanosuspension (Rabinow et al. 2007 ). With regard to the
original development aim of a generic product, this was a failure but the data dem-
onstrate nicely the possibility to target drugs via nanocrystals to the cells of the
mononuclear phagocytic system (MPS). Of high interest are for example anti-HIV
drugs to target to viruses residing in the macrophages, e.g. as shown for the drug
nevirapine (Müller, Shegokar, and Keck in press ).
There are two ways to imitate the pharmacokinetics of injected solutions. Firstly
the nanocrystals can be made small enough that they are dissolved before “meeting”
the macrophages. It was shown that i.v. injected 897 nm oridonin nanosuspensions
accumulated in the liver, whereas 103 nm nanocrystals showed a pharmacokinetics
similar to a solution (Gao et al. 2008 ). Secondly, the nanocrystal surface can be
modified analogue to the stealth liposomes generating stealth nanocrystals. A stealth
surface avoids the adsorption of e.g. opsonins which leads to the recognition by
the macrophages. Pre-requisite of this concept is that the stealth properties on the
nanocrystal surface remain during the dissolution process of the nanocrystals in
the blood. The stealth properties can be checked in vitro by analysing the protein
adsorption patterns in plasma and in serum (Lück et al. 1998 ; Lind et al. 2001 ;
Göppert and Müller 2003 ). The analytical tool is two-dimensional polyacrylamide