Abstract
Development of Exubera® (insulin powder for inhalation) presented numerous challenges as a first-in-class product. These challenges included developing (a) the first room temperature stable insulin formulation, (b) a spray-drying process to produce a fine respirable powder with the physical attributes needed for efficient aerosolization, (c) a filling and packaging process capable of accurately and reproducibly dispensing fine powders, (d) a durable inhaler that enables reliable dosing to the patient under a variety of dosing scenarios and environmental conditions, and (e) a clinical program for Type 1 and Type 2 diabetics involving parallel measurements of pulmonary function. Insulin was formulated with sodium citrate, mannitol, and glycine in a homogenous aqueous solution prior to spray drying. Spray-drying equipment was designed and scaled up, to produce powder with tight control over particle size (mean ≈ 2 µm) and moisture content (< 2 %). The resulting amorphous powder was purposely designed to provide a high glass transition temperature (T g) that minimized insulin mobility (thus reactivity). Fine powder handling and packaging technology was developed to reproducibly fill blister packages containing 1.7 and 5.1 mg of powder (1 and 3 mg insulin per blister, respectively). The heat-sealed perimeter of the blisters prevented moisture ingress and provided room temperature storage for 18 and 24 months in the USA and EU, respectively. The Exubera® inhaler was designed for reproducible delivery and simple 5-step operation: (1) extension of the device chamber, (2) insertion of blister, (3) manual pump of handle to compress a defined volume of air (as the energy source for aerosolization), (4) button actuation to release the compressed air and thereby extract the insulin powder from the blister and disperse it as a fine aerosol into the chamber, and (5) rotation of the chamber mouthpiece to enable dose administration via inhalation of the standing aerosol cloud. Exubera® delivered insulin to the deep lung where it was absorbed into the blood stream with similar reproducibly and effectiveness as subcutaneous injections. Exubera® gained FDA and EMA approval in 2006, validating the technological and clinical efforts of Pfizer, Nektar, and Sanofi-Aventis. However, Exubera® was not a commercial success and was removed from the market in 2007. Lessons learned from the technology integration, the partnership between technology provider and sponsor, and the brief market experience are discussed.
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Acknowledgments
The authors would like to thank the Exubera® team members within Pfizer, Nektar, and Sanofi-Aventis for their technical inspiration and teamwork.
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Stevenson, C., Bennett, D. (2014). Development of the Exubera® Insulin Pulmonary Delivery System. In: das Neves, J., Sarmento, B. (eds) Mucosal Delivery of Biopharmaceuticals. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-9524-6_21
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DOI: https://doi.org/10.1007/978-1-4614-9524-6_21
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