Inhaled insulin administration is the first approved alternative route of insulin delivery that does not require injection in the United State. Pulmonary delivery is considered the most promising alternative administration route for proteins and peptides such as leuprolide acetate, calcitonin, insulin and interferon-alpha due to a number of advantages: the lower dose is needed to achieve the same therapeutic benefit; degradation within the gastrointestinal tract is avoided; reduction of unwanted systemic side effects, and more rapid onset of action.

Despite the US FDA approval of inhaled insulin, it is recognized that consistency in lung deposition still needs optimization. Factors affecting the deposition efficiency of aerosol insulin include the aerodynamic diameter, surface morphology, formulation, inspiratory flow rate and inhaled volume. These factors may be controlled by the development of particle engineering techniques. In this study we have produced micro-particles of insulin with stabilizers for pulmonary delivery using a supercritical antisolvent process. The most frequently used stabilizer for aerosol insulin is mannitol. Published studies show that insulin/mannitol particles produced are irregular and needle-shaped. Although needle-shaped particles result in higher dose delivery (for the same aerodynamic diameter), the dose reproducibility is poor.

In this work, we improved aerosol delivery efficiency by modifying the shape of insulin particles, achieved by changing the nature and quantity of stabilizers and other additives. The secondary structure stability of insulin produced is also examined. Our scanning electron microscopy (SEM) results indicate that insulin/mannitol/trehalose particles produced by supercritical antisolvent process under appropriate conditions were relatively uniform, more spherical, less cohesive, and agglomerated in an air flow, when compared to insulin/mannitol particles which formed irregular and needle-shaped particles. The mass median aerodynamic diameter of insulin/mannitol/trehalose particles obtained from an aerodynamic particle sizer (APS) was 2.25ìm which is suitable for use in inhalation therapy. The particle size distributions determined after dispersion from a dry powder inhaler were symmetrical and consistent, indicating a low tendency for agglomeration. Fourier transform infrared (FTIR) analysis showed that the secondary structures of insulin/mannitol/trehalose particles precipitated from a dimethylformamide (DMF) solvent were only slightly affected by the supercritical antisolvent process for the conditions studied here. Analyses using x-ray photoelectron spectroscopy (XPS) and micro-orifice uniform deposit impactor (MOUDI) are performed to determine the distribution of insulin within the particles and whether this distribution changes with particles size.