Development of Chondroitin Sulfate ‑ Stabilized PLGA Microspheres of Exenatide via Polarity Gradient Extraction.
The study presents a stable microsphere formulation of exenatide with controlled release for over one month, but clinical implications in humans are not established.
Where it sits
this study against the rest of the exenatide corpusSummary and findings
This study developed a poly (lactide-co-glycolide) based injectable microsphere formulation of exenatide. 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.
Background
This paper addresses the challenge of developing a stable and effective delivery system for exenatide, a GLP-1 receptor agonist. Prior research has highlighted the need for sustained release formulations to improve therapeutic outcomes. The study is significant as it explores a novel microsphere formulation that could enhance the pharmacokinetic profile of exenatide.
Methods
The study utilized a coacervation and in-oil drying process to create poly (lactide-co-glycolide) microspheres. Critical parameters affecting stability, drug loading, and release were evaluated. The formulation included chondroitin sulfate at concentrations of 0.5-2% w/w, with stability assessed over 24 months.
Results
The primary endpoint showed drug loading up to 4.7% w/w. The formulation achieved an initial burst release of less than 1%. Stability was confirmed for 24 months at 2-8 °C with minimal loss of assay content. In vitro release demonstrated controlled release for over one month, correlating with in vivo outcomes.
Interpretation
While the study presents promising results regarding the formulation's stability and release profile, the clinical significance remains uncertain due to the lack of human data. The effect sizes observed in animal studies may not translate directly to human populations, and the study's focus on formulation rather than clinical efficacy limits its applicability in practice.
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.