Solid lipid nanoparticles (SLN)--effects of lipid composition on in vitro degradation and in vivo toxicity.

Solid lipid nanoparticles (SLN) composed of two different lipid matrices were produced to assess their in vivo toxicity in mice. Matrix substances were (i) Compritol (glycerol behenate), a physiological lipid with GRAS status (generally recognized as safe [FDA]), and (ii) cetyl palmitate, a less physiological compound. Physicochemical data proved the suitability of SLN batches for intravenous administration. To assess the in vivo toxicity of produced batches, 400 microl SLN dispersion (lipid content 10% [m/m]) were administered to mice via a bolus injection for six times within a period of 20 days (high dose administration). Additionally, a multiple low dose administration was performed with Compritol-SLN as well (200 microl SLN dispersion, lipid content 2.5% [m/m]). Hepatic and splenic tissues were analysed histologically. In vivo results were dependent on the lipid matrix, as well as on the dose administered. For cetyl palmitate containing SLN no pathological results were obtained, while high dosed Compritol containing formulations led to accumulation of the lipid in liver and spleen and subsequently to pathological alterations. These alterations were found to be partially reversible within six weeks after completing intravenous administration. Liver architecture was nearly recovered. In contrast, low dosed Compritol SLN were well tolerated. Lipid accumulation and pathological alterations of high dosed Compritol SLN were attributed to the slow degradation of the Compritol matrix which could be shown by performing in vitro studies in human plasma.

Phagocytic uptake and cytotoxicity of solid lipid nanoparticles (SLN) sterically stabilized with poloxamine 908 and poloxamer 407.

Solid lipid nanoparticles (SLN) as alternative intravenous colloidal drug carriers were produced by high pressure homogenisation of melted lipids (glycerolbehenate, cetylpalmitate). Their surface was modified by using hydrophilic poloxamine 908 and poloxamer 407 blockcopolymers in order to reduce the phagocytic uptake by the reticuloendothelial system (RES) after i. v. injection. The phagocytosis reducing effect of the polymers was investigated in vitro in cultures of human granulocytes, uptake was quantified by chemiluminescence. Modification of the SLN with poloxamine 908 and poloxamer 407 reduced the phagocytic uptake to appr. 8-15% compared to the phagocytosis of hydrophobic polystyrene particles. The modified SLN proved more efficient in avoiding phagocytic uptake than polystyrene particles surface-modified with these blockcopolymers (48% and 38%, respectively). Viability determinations revealed the SLN to be 10 fold less cytotoxic than polylactide nanoparticles and 100 fold less than butylcyanoacrylate particles.