Development of Chondroitin Sulfate ‑ Stabilized PLGA Microspheres of Exenatide via Polarity Gradient Extraction.

This study presents a novel microsphere formulation of exenatide with promising stability and controlled release characteristics, but clinical relevance remains to be established.

Summary and findings

This study describes the development of a sustained release injectable microsphere formulation of exenatide using a coacervation process. The formulation achieved drug loading up to 4.7% w/w and demonstrated controlled release for over one month. Stability was maintained for 24 months at 2-8 °C with minimal loss of assay content.

Abstract

The present work describes the development and optimization of a poly (lactide-co- glycolide) based sustained release injectable microsphere formulation of exenatide using a coacervation and in oil drying process. The internal phase composition, containing exenatide and stabilizer, were evaluated to identify critical parameters affecting stability, drug loading, particle morphology, and burst release of exenatide. Incorporation of chondroitin sulfate(0.5-2% w/w), formed stable uniform coacervates providing consistent particle size distribution, drug loading up to 4.7% w/w, initial burst (<1%) and impurities, with "shrunken" microsphere morphology. The secondary emulsification temperature of 2-8 °C produced smaller and more uniform particles. A gradient quenching process for hardening of microspheres using n heptane: diethyl ether (1:9) to (10:0) provided low porosity and burst release relative to n-Heptane alone. The drying and lyophilization conditions reduced residual solvent levels (<5000 ppm or below quantitation) and improved its wetting characteristics. The formulation remained stable for 24 months at 2-8 °C, with minimal loss of assay content. In vitro release showed controlled release for over one month. This translated into approximately 28 days of drug exposure in rat pharmacokinetic studies and sustained glycemic control for 28 days in a db/db mice, thus, correlating microsphere erosion, in‑vitro release, and in‑vivo outcomes. This study provides insight into the manufacturing process dynamics.

Key findings

• Drug loading up to 4.7% w/w.
• Initial burst release <1%.
• Formulation remained stable for 24 months at 2-8 °C.
• Controlled release for over one month.
• Approximately 28 days of drug exposure in rat pharmacokinetic studies.
• Sustained glycemic control for 28 days in db/db mice.

Limitations

• Not reported in abstract.
• Animal models may not fully predict human outcomes.
• Focus on formulation development without clinical trial data.
• Short follow-up duration for in vivo studies.

Elsewhere in the Exenatide corpus