Mechanisms controlling protein release from lipidic implants: Effects of PEG addition
ABSTRACT Different types of tristearin-based implants for controlled rh-interferon alpha-2a (IFN-alpha) release were prepared by compression and thoroughly characterised in vitro. Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was added as a co-lyophilisation agent for protein stabilisation and different amounts of polyethylene glycol (PEG) as efficient protein release modifier. To get deeper insight into the underlying mass transport mechanisms, the release of IFN-alpha, HP-beta-CD and PEG into phosphate buffer pH 7.4 was monitored simultaneously and appropriate analytical solutions of Fick's second law of diffusion were fitted to the experimental results. Importantly, the addition of only 5-20% PEG to the lipidic implants significantly altered the resulting protein release rates and the relative importance of the underlying mass transport mechanisms. The release of IFN-alpha from PEG-free implants was purely diffusion controlled. In contrast, in PEG-containing devices other phenomena were also involved in the control of protein release: the IFN-alpha release rate remained about constant over prolonged periods of time and the total amounts of mobile IFN-alpha increased. Interestingly, the release of PEG itself as well as of HP-beta-CD from the implants remained purely diffusion controlled, irrespective of the amount of added PEG. Thus, different mass transport mechanisms govern the release of the drug, co-lyophilisation agent and release modifier out of the lipidic implants.
- SourceAvailable from: Henderik Frijlink[Show abstract] [Hide abstract]
ABSTRACT: Parenteral protein delivery requires preservation of the integrity of proteins and control over the release kinetics. In order to preserve the integrity, parenteral protein delivery formulations typically need to be processed at low temperatures. Therefore, we synthesized a novel low melting biodegradable hydrophilic multiblock copolymer composed of poly (ethylene glycol) and poly (ε-caprolactone) to allow extrusion at relatively low temperatures. We investigated the extrusion characteristics of this polymer and explored a strategy how to control the release of the model protein lysozyme from small diameter extruded implants. It was found that the polymer could be well extruded at temperatures as low as 55 ˚C. Moreover, lysozyme remained active both during extrusion as well as during release. Lysozyme release kinetics could be tailored by the co-incorporation of an oligosaccharide, inulin, which functions as a pore-forming excipient. It was concluded that this hydrophilic multiblock copolymer has promising characteristics for the preparation by melt extrusion of protein delivery implants with a release profile that is sustained over a period of more than 7 months.European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 05/2013; 49(4). DOI:10.1016/j.ejps.2013.05.011 · 3.01 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The aim of this study was to investigate and compare the immunogenicity of liposome-forming, sustained release lipid implants containing either an alpha-galactosylceramide (alpha-GalCer) analogue, imiquimod or Quil-A (QA) as adjuvants. Ovalbumin (OVA) was used as a model antigen. Groups of C57Bl/6 mice were subcutaneously immunised with lipid implants containing one of the adjuvants, or inoculated with OVA in alum. The expansion of CD8+ and CD4+ transgenic T cells was analysed to assess the ability of these implants to stimulate cell-mediated immunity. In addition, the production of OVA-specific IgG antibodies was determined. QA-containing lipid implants were more efficient in the stimulation of CD8+ T cells and IgG antibodies than the two immunomodulators alpha-GalCer and imiquimod. These results suggest that, using this immunisationprotocol and dose of immunomodulators, QA was superior to imiquimod and alpha-GalCer.Pharmazie 10/2008; 63(9):686-92. DOI:10.1691/ph.2008.8072 · 1.00 Impact Factor