PubMed · 9370650
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V Pink. 1997-09-24. Getting needled.. https://doi.org/10.7748/ns.12.1.21.s40
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Protein-loaded dextran microspheres were prepared by a water-in-water emulsion technique. With this technique, an aqueous solution of methacrylated dextran (dex-MA) is emulsified in an aqueous solution of poly(ethylene glycol) (PEG). Subsequently, the dispersed dex-MA phase is crosslinked by radical polymerization of the dextran-bound methacryloyl groups. This method renders microspheres with a hydrogel character of which the crosslink density can be controlled by the water content and the degree of substitution of the dex-MA (DS, the number of methacrylates per 100 glucopyranose residues). If an IgG solution was added to the dex-MA/PEG aqueous system prior to the polymerization reaction, the protein could be encapsulated in the dextran microspheres with a high yield (88-98%). The release of IgG was studied as a function of the water content, the DS and the degradation rate of the microspheres. The microspheres were rendered degradable by co-encapsulation of an endo-dextranase. Non-degrading microspheres mainly showed a burst release, which decreased with increasing crosslink density. By either a low water content (50%, w/w, or lower) or a high DS (DS 13), it was possible to reduce the burst release to about 10%, meaning that almost complete entrapment of the protein could be achieved. The release of IgG from degrading microspheres was predominantly dependent on the DS and the amount of encapsulated dextranase. No differences in release of IgG from microspheres with and without dextranase were observed at high DS (DS 13). This was ascribed to the inability of the enzyme to degrade these microspheres. On the other hand, the entrapped protein was completely released from enzymatically degrading microspheres with a DS 4. Moreover, the release rate of IgG was proportional to the degradation rate of these microspheres (depending on the amount of co-encapsulated dextranase). Interestingly, an almost zero-order release was observed from these microspheres for periods up to 30 days.
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The purpose of this study was to test the utility of infrared (IR) spectroscopy to determine protein secondary structure in biodegradable microspheres. Encapsulation of proteins within biodegradable polymers, [e.g. poly(lactic-co-glycolic acid) (PLGA)] for controlled drug release has recently been the subject of intense research effort. The ability to assess protein integrity after microsphere production is necessary to successfully produce microspheres that release native proteins. We used IR spectroscopy, a noninvasive method-as opposed to conventional organic solvent extraction or in vitro release at elevated temperature-to assess the secondary structure of recombinant human growth hormone (rhGH) within dry and rehydrated microspheres. PLGA microspheres containing rhGH with different excipients were prepared by a conventional double-emulsion method. The protein IR spectra indicated that the encapsulation process could perturb the structure of rhGH and that excipients could inhibit this damage to varying degrees. A strong positive correlation was found between intensity of the dominant alpha-helical band in the spectra of rhGH in rehydrated microspheres and the percent monomer released from microspheres during incubation in buffer. We also studied microspheres prepared with zinc-precipitated rhGH. The addition of Zn2+ during microsphere processing partially inhibited protein unfolding and fostered complete refolding of rhGH upon rehydration. In conclusion, IR spectroscopy can serve as a valuable tool to assess protein structure within both dried and rehydrated microspheres.