Sustained release of insulin from insoluble inhaled particles

✍ Scribed by Rita Vanbever; Abdellaziz Ben-Jebria; Jeffrey D. Mintzes; Robert Langer; David A. Edwards

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 175 KB
• Volume: 48
• Category: Article
• ISSN: 0272-4391
• DOI: 10.1002/(sici)1098-2299(199912)48:4<178::aid-ddr5>3.0.co;2-i

✦ Synopsis

Conventional slow-acting insulin preparations for subcutaneous injection, e.g., suspensions of the complex with protamine and/or zinc, were reformulated as dry powders for inhalation and the insoluble aerosol tested for providing sustained insulin plasma levels. Large porous particles made of lactose, albumin, and dipalmitoylphosphatidylcholine, and incorporating insulin, protamine, and/or zinc chloride were prepared using spray-drying. Integrity of insulin after spray-drying and insulin insolubilization in spraydried particles was verified in vitro. The pharmacokinetic profile of the formulation delivered by inhalation and subcutaneous injection was assessed in vivo in the rat. The formulation process of insulin as dry powders did not alter insulin integrity and did not impede, in most cases, insulin insolubilization by protamine and/or zinc. Large porous insulin particles presented 7 µm mass mean geometric particle diameters, 0.1 g/ cm 3 bulk powder tap densities and theoretical aerodynamic diameters suitable for deep lung deposition (in the range of 2.2-2.5 µm). The dry powders exhibited 40% respirable fractions in the Andersen cascade impactor and 58-75% in the Aero-Breather™. Insoluble inhaled insulin provided sustained insulin plasma levels for half a day, similar to injected insulin, and exhibited a bioavailability of 80.5% relative to subcutaneous injection of the same formulation.