Insulin-loaded poly-l-lactide porous microspheres prepared in supercritical CO2 for pulmonary drug delivery

• An emulsion-combined precipitation of compressed CO2 antisolvent process was adopted.
• The inhalable insulin-loaded poly-l-lactide porous microspheres were produced.
• Insulin disposed of the supercritical process retained a good hypoglycemic activity.
• The porous microspheres could realize a sustained-release of insulin.

The insulin-loaded poly-l-lactide porous microspheres (INS-PLLA PMs) were successfully developed in an emulsion-combined precipitation of compressed CO2 antisolvent (PCA) using ammonium bicarbonate (AB) as a porogen. The resulting INS-PLLA PMs exhibited a rough and porous structure with a geometric mean diameter (Dg) of 15.62 μm, an aerodynamic diameter (Da) of 4.31 μm, a fine particle fraction (FPF) of 65.57% and good aerosolization characteristics. The physicochemical characterization reveals that no chemical changes occurred on INS-PLLA PMs, while minor structural changes existed in insulin. The result of circular dichroism (CD) spectroscopy demonstrates a slight change happened in the secondary structure of insulin, however, the bioactivity verification test shows that the hypoglycemic activity of insulin from INS-PLLA PMs was well maintained, which shows no significant difference from the raw insulin. The fluorescent image of INS-PLLA PMs demonstrates that the insulin was homogeneously distributed in the matrix, and INS-PLLA PMs displayed a sustained-release effect. Furthermore, INS-PLLA PMs with almost no organic residue could promote the safety and suitability for pulmonary delivery of protein drugs. This study indicates that emulsion-combined PCA process is an effective and benign technology to produce INS-PLLA PMs, which have potential in the application of pulmonary drug delivery for treatment of diabetes.

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