Influence of Stabilizers on the Physicochemical Characteristics of Inhaled Insulin Powders Produced by Supercritical Antisolvent Process

Purpose To examine the effect of stabilizers on aerosol physicochemical characteristics of inhaled insulin particles produced using a supercritical fluid technology. Materials and Methods Insulin with stabilizers such as mannitol and trehalose was micronized by aerosol solvent extraction system (ASES). The supercritically-micronized insulin particles were characterized for size, shape, aerosol behavior, crystallinity and secondary structure. Results Experimental results indicated that when insulin was incorporated with the most commonly used stabilizer mannitol (insulin/mannitol: 15/85 wt.%, designated IM), the particles formed were irregular and needle-shaped and had a tendency to agglomerate. With the incorporation of a second stabilizer trehalose (insulin/mannitol/trehalose: 15/70/15 wt.%, designated IMT), the particles were relatively uniform, more spherical, less cohesive, and less agglomerated in an air flow, when compared to IM particles. The mass median aerodynamic diameter of the IMT particles was 2.32 μm which is suitable for use in inhalation therapy. In vitro deposition test using micro-orifice uniform deposit impactor showed 69 ± 7 wt.% of the IMT particles was deposited in stage 3, 4, 5 and 6 while 41 ± 15 wt.% of the IM particles was deposited in the same stages. In terms of insulin stability, secondary structures of insulin particles were not adversely affected by the ASES processing studied here. Conclusions When properly formulated (as in IMT particles), ASES process can produce particles with appropriate size and size distribution suitable for pulmonary insulin delivery.