Abstract
The aim of this study was to investigate the effects of various stabilizers on the encapsulation efficiency and release of exenatide-loaded PLGA (poly(lactic-co-glycolic acid)) microspheres prepared by the water-in-oil-in-water (W/O/W) solvent evaporation (SE) method. It was shown that the stabilizers affected exenatide stability in aqueous solutions, at water/dichloromethane interfaces, on PLGA surfaces, or during freeze-thawing and freeze-drying procedures. Sucrose predominantly reduces instability generated during freeze-thawing and freeze-drying. Phenylalanine prevents the destabilization at the water–dichloromethane (DCM) interface through decreased adsorption. Poloxamer 188 enhances stability in aqueous solutions and prevents adsorption to PLGA. Proline and lysine decrease adsorption on PLGA surfaces. Fourier transform infra-red spectroscopy (FT-IR) was used to find the molecular interaction of additives with exenatide or PLGA. Additives used in stability assessments were then added stepwise into the inner or outer water phase of the W/O/W double emulsion, and exenatide-loaded microspheres were prepared using the solvent evaporation method. The effect of each stabilizer on the encapsulation efficiency and release behavior of microspheres correlated well with the stability assessment results, except for the negative effect of poloxamer 188. Particle size analysis using laser diffractometry, scanning electron microscopy (SEM), water vapor sorption analysis, differential scanning calorimetry (DSC), and circular dichroism (CD) spectroscopy were also employed to characterize the prepared exenatide-loaded PLGA microsphere. This study demonstrated that an adequate formulation can be obtained by the study about the effect of stabilizers on peptide stability at the preformulation step. In addition, it can help to overcome various problems that can cause the destabilization of a peptide during the microsphere-manufacturing process and sustained drug release.
Highlights
Many peptide drugs have been developed into commercialized medicines using PLGA (poly(lactic-co-glycolic acid)) microsphere technology to enable long-term application through sustained release
We examined the effects of a variety of components, such as carbohydrates, amino acids, and amphipathic surfactants, as stabilizers on the stability of exenatide in aqueous solution and the water-in-oil (W/O) interface
After evaluation of the encapsulation efficiency (EE) and release behavior of exenatide-loaded PLGA microspheres (ELPM) prepared by the W/O/W solvent evaporation (SE) method, we looked for a rational correlation of the stability test results as pre-formulation procedures with the stability of exenatide during microsphere preparation and drug release
Summary
Many peptide drugs have been developed into commercialized medicines using PLGA (poly(lactic-co-glycolic acid)) microsphere technology to enable long-term application through sustained release. For such development, stability improvements to avoid peptide degradation and to ensure optimized sustained drug release are of particular interest [1]. In order to solve the urgent instability problem of current marketed peptide medicines, the best way may be to improve by using FDA (Food and Drug Administration)-approved and applicable inactive ingredients. If information on the stabilizing effect of the additives is obtained at the preformulation step in advance, it can be applied quickly to settle an instability issue
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