Sustained-release delivery of octreotide from biodegradable polymeric microspheres

Abstract

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.

Fig. 1

a Serum concentration vs. time curves of octreotide after I.M. administrations of three Oakwood formulations and Sandostatin LAR 20 mg at the dose of 3 mg per rat; and b the data collected during the first 6 h after injection. Each point represents mean±S.D. (n = 6 or 7): open circle Oakwood formulation 1; open square Oakwood formulation 2; open upright triangle Oakwood formulation 3; open diamond Sandostatin LAR^® 20 mg

Fig. 2

Simulation of octreotide serum concentration following single I.M. administration of sustained-release microsphrere formulations at the dose of 3 mg per rat, and the data collected during the first 6 h after injection (inset). Each point represents mean±S.D. (n = 6 or 7): a Oakwood formulation 1; b Oakwood formulation 2; c Oakwood formulation 3; and d Sandostatin LAR 20 mg; filled circle experimental data; solid line simulation data

Fig. 3

Comparison of predicted octreotide serum concentration following single I.M. injections of sustained-release microsphrere formulations at the dose of 3 mg per rat. Each point represents mean±S.D. (n = 6 or 7): a Oakwood formulation 1 and Sandostatin LAR^® 20 mg; b Oakwood formulation 2 and 3; filled circle predicted data for formulation 1; open circle predicted data for Sandostatin LAR^®; filled square predicted data for formulation 2; open square predicted data for formulation 3; solid line predicted curve for formulation 1; dashed line predicted curve for Sandostatin LAR^®; dash–dot–dash line predicted curve for formulation 2; dash–dot–dot–dash line predicted curve for formulation 3

Fig. 4

Computer simulation of octreotide serum concentration following repeated I.M. injections of sustained-release microsphrere formulations every 28 days or 42 days at the dose of 3 mg per rat: a Oakwood formulation 1; b Oakwood formulation 2; c Oakwood formulation 3; d Sandostatin LAR^® 20 mg; solid line simulation data for every 28 days; broken line simulation data for every 42 days