In Vivo Tolerability

NLCs are a rather young development; the patents were filed in 1999 explaining why limited data are available. However, again one can refer to the results obtained with

0,001 0,01

SLN-concentration [%]

Figure 6. IL-6 production of macrophages treated with different SLN formulations compared to Lipofundin-treated macrophages. Non-treated macrophages are defined as 1. Modified with permission from [80], N. Schöler, Ph.D. Dissertation, Freie Universität Berlin, 2001.

SLNs. The first studies were performed in mice by injecting extremely high doses of SLNs intraveneously (1.33 g lipid/kg body weight). In these studies, large volumes of SLNs were injected into mice, which means 0.4 mL [56]. Assuming a blood volume of about 2 mL/mouse, about 20% of the blood volume was injected as highly concentrated SLN dispersion. Calculating the injected amount on the basis of medium human body weight (75 kg) would mean that 100 g of solid lipid were injected as a bolus. Of course, such a calculation cannot be done in a strict sense, but illustrates the heavy lipid load in this tolerability study. Injected particles were made from Compritol, and as a second system made from cetyl palmitate. Only with 10% Compritol dispersions was an increase in the weight of the liver and spleen observed, which was reversible after a few weeks. Cetyl palmitate did not lead to any changes. The difference in vivo was explained by the difference in the degradation velocity. Compritol as a lipid with a high fraction of triglycerides is degraded much more slowly; therefore, there is an increase in liver weight. Cetyl palmitate is degraded much faster, thus avoiding a change in the liver weight. This is also a well-known phenomenon when comparing the degradation of LCT and MCT oils. LCT oils are degraded more slowly; during long-term parenteral nutrition, they can increase the liver weight [57]. Transferring these results to NLC means that basically NLCs are even better tolerated than SLNs because they contain fast degrading oils as one component.

Recently, tissue tolerability studies were performed in chickens. SLN particles made from different lipids and stabilized with different surfactants were injected in the pectoral muscle of chickens [58]. The tolerability was compared to injected Freund's incomplete adjuvants. With the SLNs, no or very little tissue alteration was observed, much less than described, for example, for polymeric particles in the literature (of course, distinctly less compared to Freund's incomplete adjuvants). The tolerability was not at all or very little affected by the nature of the lipid; rather, there was a size effect (larger particles disturbed the tissue more Fig. 7, right). From this, it can also be concluded that NLCs will have a similar excellent tolerability.

■ Cetyl palmitate

■ solid paraffin

Figure 7. Right: foci of tissue alterations of the pectoral musculature (arrow) after injection of larger Compritol SLN. Left: no tissue alterations are found after injection of control.
0 0

Post a comment