Sustained-release delivery of octreotide from biodegradable polymeric microspheres.

The study reports on the drug release behavior of a potent synthetic somatostatin analogue, octreotide acetate, from biocompatible and biodegradable microspheres composed of poly-lactic-co-glycolic acid (PLGA) following a single intramuscular depot injection. The serum octreotide levels of three Oakwood Laboratories formulations and one Sandostatin LAR(®) formulation were compared. Three formulations of octreotide acetate-loaded PLGA microspheres were prepared by a solvent extraction and evaporation procedure using PLGA polymers with different molecular weights. The in vivo drug release study was conducted in male Sprague-Dawley rats. Blood samples were taken at predetermined time points for up to 70 days. Drug serum concentrations were quantified using a radioimmunoassay procedure consisting of radiolabeled octreotide. The three octreotide PLGA microsphere formulations and Sandostatin LAR(®) all showed a two-phase drug release profile (i.e., bimodal). The peak serum drug concentration of octreotide was reached in 30 min for all formulations followed by a decline after 6 h. Following this initial burst and decline, a second-release phase occurred after 3 days. This second-release phase exhibited sustained-release behavior, as the drug serum levels were discernible between days 7 and 42. Using pharmacokinetic computer simulations, it was estimated that the steady-state octreotide serum drug levels would be predicted to fall in the range of 40-130 pg/10 µL and 20-100 pg/10 µL following repeat dosing of the Oakwood formulations and Sandostatin LAR(®) every 28 days and every 42 days at a dose of 3 mg/rat, respectively.

Assessment of protein release kinetics, stability and protein polymer interaction of lysozyme encapsulated poly(D,L-lactide-co-glycolide) microspheres.

Using lysozyme as a model protein, this study investigated protein stability, protein--polymer interaction in different release media and their influence on protein release profile and in vitro--in vivo correlation. Lysozyme was microencapsulated into PLGA 50:50 by a double emulsion--solvent extraction/evaporation method. Protein stability, protein--PLGA adsorption and protein in vitro release were studied in various test media. Differential scanning calorimetry analysis showed lysozyme to be most conformationally stable in pH 4.0 acetate buffer with highest T(m) at 77.2 degree C and DeltaH(cal) 83.1 kcal/mol. Lysozyme exhibited good stability in pH 2.5 glycine buffer with T(m) at 63.8 degree C and DeltaH(cal) 69.9 kcal/mol. In pH 7.4 phosphate-buffered saline (PBS), lysozyme showed a trend toward aggregation when the temperature was elevated. When PLGA polymer was incubated with lysozyme in the various buffers, adsorption was found to occur in PBS only. The adsorption severely limited the amount of lysozyme available for release from microspheres, resulting in slow and incomplete release in PBS. In contrast, the release of the microspheres in acetate and glycine buffers was complete within 40 and 70 days, respectively. Radiolabeled lysozyme blood levels in rats from the microspheres correlated qualitatively well with in vitro release in glycine buffer as a release medium. This study suggests that protein stability and adsorption are critical factors controlling protein release kinetics and in vitro--in vivo correlation of PLGA microspheres.