New insight into the role of XXXX acting as protein release modifier in lipidic implants.

@entity21802 @entity970 @entity1391 @entity214 @entity3027 @entity968
PURPOSE: It has recently been shown that the addition of @entity968 ( @entity970 ) 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 @entity970 acts. It was the aim of this study to elucidate the effect of @entity970 in a mechanistic manner. MATERIALS AND METHODS: rh-interferon alpha-2a ( @entity3027 )-loaded, @entity21802 -based implants containing various amounts of @entity970 were prepared by compression. Protein and @entity970 release was monitored in @entity1391 buffer pH 4.0 and pH 7.4. @entity3027 solubility and stability were assessed by reverse phase and size exclusion HPLC, @entity214 PAGE, fluorescence and FTIR. RESULTS: Importantly, in presence of @entity970 @entity3027 was drastically precipitated at pH 7.4. In contrast, at pH 4.0 up to a @entity970 concentration of 20% no precipitation occurred. These fundamental effects of @entity970 on protein solubility were reflected in the release kinetics of @entity3027 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 @entity3027 release was governed by pure diffusion at pH 4.0, irrespective of the @entity970 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. CONCLUSIONS: For the first time it is shown that the release of pharmaceutical proteins can be controlled by an in-situ precipitation within inert matrices.
