Mechanisms controlling protein release from lipidic implants: effects of PEG addition.
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.
Herrmann
Sandra
S
Department of Pharmacy, Ludwig-Maximilians-University Munich, Butenandtstrasse 5, 81377 Munich, Germany. sandra.herrmann@cup.uni-muenchen.de
Winter
Gerhard
G
Mohl
Silke
S
Siepmann
Florence
F
Siepmann
Juergen
J
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002021:Buffers; D002626:Chemistry, Pharmaceutical; D004058:Diffusion; D004337:Drug Carriers; D004339:Drug Compounding; D004343:Drug Implants; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D005612:Freeze Drying; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000737:chemistry*; D007700:Kinetics; D008055:Lipids / Q000737:chemistry*; D008956:Models, Chemical; D011092:Polyethylene Glycols / Q000737:chemistry*; D011994:Recombinant Proteins; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D014280:Triglycerides / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000737:chemistry
D002021:Buffers; D004337:Drug Carriers; D004343:Drug Implants; D005079:Excipients; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008055:Lipids; D011994:Recombinant Proteins; D014280:Triglycerides; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D011092:Polyethylene Glycols; C022618:tristearin