New insight into the role of polyethylene glycol acting as protein release modifier in lipidic implants

It has recently been shown that the addition of polyethylene glycol 6000 (PEG) to lipidic implants fundamentally affects the resulting protein release kinetics and moreover, the underlying mass transport mechanisms (Herrmann, Winter, Mohl, F. Siepmann, & J. Siepmann, J. Control. Release, 2007). However, it is yet unclear in which way PEG acts. It was the aim of this study to elucidate the effect of PEG in a mechanistic manner.

rh-interferon alpha-2a (IFN-alpha)-loaded, tristearin-based implants containing various amounts of PEG were prepared by compression. Protein and PEG release was monitored in phosphate buffer pH 4.0 and pH 7.4. IFN-alpha solubility and stability were assessed by reverse phase and size exclusion HPLC, SDS PAGE, fluorescence and FTIR.

Importantly, in presence of PEG IFN-alpha was drastically precipitated at pH 7.4. In contrast, at pH 4.0 up to a PEG concentration of 20% no precipitation occurred. These fundamental effects of PEG on protein solubility were reflected in the release kinetics of IFN-alpha from the tristearin implants: At pH 7.4 the protein release rates remained nearly constant over prolonged periods of time, whereas at pH 4.0 high initial bursts and continuously decreasing release rates were observed. Interestingly, it could be shown that IFN-alpha release was governed by pure diffusion at pH 4.0, irrespective of the PEG content of the matrices. In contrast, at pH 7.4 both--the limited solubility of the protein as well as diffusion through tortuous liquid-filled pores--are dominating.

For the first time it is shown that the release of pharmaceutical proteins can be controlled by an in-situ precipitation within inert matrices.