In situ forming risperidone implants: Effect of PLGA attributes on product performance.

Area of Science:

• Pharmaceutical Sciences
• Biomaterials Science
• Drug Delivery Systems

Background:

• Injectable, long-acting in situ forming implants offer unique advantages but face limited commercial availability.
• Poly(lactide-co-glycolide) (PLGA) is a key polymer in these formulations, and understanding its properties is crucial for product development.
• Existing research has not fully elucidated how subtle variations in PLGA attributes impact the performance of these drug delivery systems.

Purpose of the Study:

• To investigate the influence of specific poly(lactide-co-glycolide) (PLGA) attributes on the in vitro and in vivo performance of in situ forming implants.
• To evaluate the impact of molecular weight, lactide:glycolide ratio, blockiness, and end group on risperidone-loaded implant behavior.
• To provide insights aiding the development of novel and generic long-acting injectable formulations.

Main Methods:

• Formulations based on poly(lactide-co-glycolide) (PLGA) with varied molecular weight, lactide:glycolide ratio, and end groups were prepared.
• In vitro drug release was assessed using an adapter-based USP 2 method, with Perseris (risperidone) as the reference listed drug.
• In vivo pharmacokinetic profiles were determined in a rabbit model, followed by deconvolution (Loo-Riegelman method) to obtain in vivo release profiles.

Main Results:

• Minor variations in poly(lactide-co-glycolide) (PLGA) molecular weight (5 KDa difference), lactide:glycolide ratio (5% variation), and end-cap (acid vs. ester) significantly altered both in vitro and in vivo release.
• Higher molecular weight, higher lactide:glycolide ratio, and ester end-capped PLGA resulted in prolonged drug release durations.
• Varying blockiness within the tested range did not significantly impact in vitro or in vivo release profiles; in vitro-in vivo correlation was not achieved.

Conclusions:

• Poly(lactide-co-glycolide) (PLGA) properties, particularly molecular weight, lactide:glycolide ratio, and end group, are critical determinants of in situ forming implant performance.
• The study highlights significant differences in in vitro and in vivo release kinetics, preventing direct in vitro-in vivo correlation due to disparate phase separation and swelling.
• This research provides foundational knowledge for optimizing poly(lactide-co-glycolide) (PLGA) based in situ forming implants, facilitating the development of improved long-acting injectable drug delivery systems.