Enzymatic degradation of SLN—effect of surfactant and surfactant mixtures

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Abstract

Solid lipid nanoparticles (SLN) show different degradation velocities by the lipolytic enzyme pancreatic lipase as a function of their composition (lipid matrix, stabilizing surfactant). In combination with pancreatic colipase a degradation assay has been developed for studying the degradation behavior. As a measure to follow the degradation the formed free fatty acids have been analyzed using an enzymatic test. In the studies SLN degradation showed dependencies in relation to the length of the fatty acid chains in the triglycerides and the surfactants used for SLN production. The longer the fatty acid chains in the glycerides, the slower the degradation. The influence of surfactants can be degradation accelerating (e.g. cholic acid sodium salt) or a hindering, degradation slowing down effect due to steric stabilization (e.g. Poloxamer 407). As a second steric stabilizer, Tween 80 has been used and the results showed a less pronounced effect on hindering the degradation process than for Poloxamer 407. This result seems to be correlated to the number of ethyleneoxide chains in the molecule. The longer the ethyleneoxide chains are in the molecule, the more hindered is the anchoring of the lipase/colipase complex and consequently the degradation of the SLN. The result can be used to adjust degradation of SLN and consequently drug release in a controlled way.

Introduction

Solid lipid nanoparticles (SLN) could be established as an alternative particulate carrier system by various research groups (Amselm et al., 1992, Siekmann and Westesen, 1992, Boltri et al., 1995, Sjostrom et al., 1995, Müller and Lucks, 1996, Bargoni et al., 1998, Heiati et al., 1998). They combine advantages of emulsions, liposomes and polymeric nanoparticles. Similar to emulsions and liposomes they are composed of physiologically well tolerated excipients and can be produced on large industrial scale by high pressure homogenization (Müller et al., 1997, Hildebrand et al., 1998). Identical to polymeric nanoparticles their solid matrix protects incorporated active ingredients against chemical degradation and provides the highest flexibilities in the modulation of the drug release profiles. Using model drugs it could be shown, that in vitro drug release could be varied from minutes (burst release) (zur Mühlen et al., 1998) to up to 7 weeks (Mehnert et al., 1997).

Drug release in these in vitro studies took place by solid phase diffusion, the release media did not contain any enzymes. However, in vivo release will take place by diffusion and by matrix degradation. To optimize the release profiles for the in vivo situation, knowledge about the enzymatic degradation velocity of SLN is essential. Previously an SLN enzymatic degradation assay was established using a lipase/colipase complex (Olbrich, et al., 1997). It could be shown that the degradation velocity depends on the composition of the lipid matrix (Müller et al., 1996). In general, degradation velocity increased with decreasing length of the fatty acid chain length when using glycerides as lipid matrix (Olbrich et al., 1998a). In addition, the degradation of SLN based on waxes (e.g. cetylpalmitate) was found to be slower compared to glyceride matrices.

A prerequisite for the degradation of SLN after oral administration is the anchoring of the lipase/colipase complex onto the particle surface. Therefore it was expected that not only the composition of the lipid matrix, but also the nature of the stabilizing surfactant layer would be a determining factor for degradation. Compounds such as cholic acid sodium salt are known to promote the anchoring of the lipase colipase complex on surfaces (Borgström, 1975). Sterically stabilizing polymers such as the Poloxamer series are known to prevent or to hinder the absorption of large molecules such as proteins (Blunk et al., 1993). A similar effect was expected for the lipase/colipase. The aim was therefore to study the effects of different surfactants on the degradation velocity. To assess whether a desired degradation velocity can be achieved in a controlled way, mixtures of surfactants promoting degradation with surfactants slowing down the degradation rate were investigated.

Section snippets

Materials

As lipids Cetylpalmitate from Gattefossé (Weil am Rhein, Germany) and Dynasan 116 and 118 (glycerol-tripalmitate and -tristearate) from Contensio GmbH (former Hüls AG, Witten, Germany) were kindly provided as gifts. Poloxamer 407 was donated by ICI (Essen, Germany) and Lipoid E80 from Lipoid KG (Ludwigshafen/Rhein, Germany). Cholic acid sodium salt, Tween 80, lipase (Type IV) 30000 U/mg, colipase from porcine pancreas and calcium chloride dihydrate were purchased from Sigma (Deisenhofen,

Results and discussion

To study the effect of the stabilizer on the degradation velocity, SLN were produced using cholic acid sodium salt, lecithin (Lipoid E80) and the two steric stabilizers Tween 80 and Poloxamer 407. These differ in the length of the sterically stabilizing polyethylene oxide chains, being 20 units in Tween 80 and 98 units in Poloxamer 407. In combination with the differences in the molecular weights (approximately 1840 and 11500, respectively) they provide sterically stabilizing layers of a

Conclusions

The data show that the degradation velocity is substantially affected by the stabilizer used for the preparation of the SLN. Some stabilizers as cholic acid sodium salt have degradation accelerating effects, others such as Poloxamer 407 distinctly slow down the degradation velocity. Degradation velocity can be modulated by changing the surfactant ratio. The very pronounced effects of the surfactants/surfactant mixtures on the degradation velocity allow the choice of lipid for SLN production

Acknowledgements

This work was supported by the German research council (Deutsche Forschungsgemeinschaft, DFG), Grant No. Mu 10-1.

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