In vivo release kinetics of octreotide acetate from experimental polymeric microsphere formulations using oil/water and oil/oil processes

Abstract

The purpose of the present study was to characterize the in vivo release kinetics of octreotide acetate from microsphere formulations designed to minimize peptide acylation and improve drug stability. Microspheres were prepared by a conventional oil/water (o/w) method or an experimental oil/oil (o/o) dispersion technique. The dosage forms were administered subcutaneously to a rat animal model, and serum samples were analyzed by radioimmunoassay over a 2-month period. An averaged kinetic profile from each treatment group, as a result, was treated with fractional differential equations. The results indicated that poly(l-lactide) microspheres prepared by the o/o dispersion technique provided lower area under the curve (AUC) values during the initial diffusion-controlled release phase, 7.79 ng×d/mL, versus 75.8 ng×d/mL for the o/w batch. During the subsequent erosion-controlled release phase, on the other hand, the o/o technique yielded higher AUC values, 123 ng×d/mL, versus 42.2 ng×d/mL for the o/w batch. The differences observed between the 2 techniques were attributed to the site of drug incorporation during the manufacturing process, given that microspheres contain both porous hydrophilic channels and dense hydrophobic matrix regions. An o/o dispersion technique was therefore expected to produce microspheres with lower incorporation in the aqueous channels, which are responsible for diffusion-mediated drug release.

Sustained-Release Delivery of Octreotide from Biodegradable Polymeric Microspheres

“…2). The second continuous absorption phase was obtained in Oakwood formulation 2, 3 and the Sandostatin LAR ® , and the main mechanism of this phase has been suggested as polymer erosion and bulk degradation (35). However, the second and the third phase were observed in Oakwood formulation 1.…”

“…Overall, the in vivo release profile of octreotide from microspheres presented two phases, initial burst release phase due to the localization of the peptide near the surface or within pores or channels near the surface, followed by continuous release phase corresponding to the peptide entrapped in polymer matrix (35). After I.M.…”

“…During the first day, there was frequent sampling to capture the burst release. Sampling schedule was determined based on the previous reports (35). All rats had approximately 0.6-0.8 mL of blood drawn from the tail by a tail-vein nicking method at the specific time points.…”

“…The serum concentrations of octreotide were determined using a validated radioimmunoassay (RIA) method (35,36). The commercial octreotide-RIA kit (Bachem Inc., Torrance, CA) allowed for quantification of the peptide within the range of 1-125 pg; and hence, only 10 μL of serum sample was required for each tube in the analysis.…”

“…A precipitate was allowed to form in each tube and was subsequently collected by centrifugation and isolated by aspiration. A standard curve was constructed using a sigmoidal competitive binding equation provided by Graph Pad Prism ® software (GraphPad Software Inc, San Diego, CA) (35).…”