EXUBERA®: Pharmaceutical Development of a Novel Product for Pulmonary Delivery of Insulin

Abstract

Development of a product for pulmonary delivery of insulin presented significant technology challenges for this first-in-class pharmaceutical product. These included developing (a) a chemically stabilized protein, (b) a dry powder formulation exhibiting required aerosol physical characteristics, (c) low-dose powder filling and packaging technology, and (d) a mechanical device for powder dispersal and reliable dosing to the patient. The insulin drug is formulated using a novel excipient combination to create a powder with a high glass transition temperature (Tg). The high Tg minimizes insulin mobility (thus reactivity), enabling ambient storage conditions. The formulation composition results in minimal hygroscopicity, where customized packaging produced product ruggedness to humidity. The formulated insulin powder is manufactured by spray-drying. This technology was further engineered to produce the desired reproducible powder characteristics with tight control over particle size and moisture content. A solution step prior to drying assures homogeneity and minimizes dependence on the physical form of the components. Novel low-dose filling and packaging technology reproducibly meters milligram quantities of microfine powder to meet stringent quality requirements for dose control. The technology for accurate, uniform, high-throughput metering of drug powders allows for automation and is scaleable for commercial operations. Finally, the mechanical device design provides powder deagglomeration and dispersion processes in a reusable dry powder inhaler with unique characteristics. The device was designed to rely on patient-generated compressed air as the energy source. A sonic discharge of air through the novel TransJector reproducibly extracts, deagglomerates, and disperses the inhalation powder. A clear holding (spacer-type) chamber allows for patient feedback via dose visualization, and separates powder dispersal from the inspiratory effort. The EXUBERA [Pfizer (New York, NY) and sanofi-aventis (Paris, France)] product provides insulin into the bloodstream with similar reproducibly and effectiveness as subcutaneous injections.

Dry powder inhalation: past, present and future

“…This resulted in the development of active DPIs, like the inhalers of the Spiros ® platform (Dura Pharmaceuticals), which have a battery-operated propeller [43] and the Exubera ® insulin inhaler (Pfizer) which utilizes pressurized air from a hand piston for active powder dispersion [44]. Such inhalers basically deliver a patient (i.e.…”

Nanomedicine in pulmonary delivery

“…111 Recently, liposomal dry powder formulations have been intensively examined in order to successfully circumvent these issues. 72,[112][113][114] Liposomal dry powder formulations have been shown to be very promising in the delivery of various types of pulmonary drugs and some of these formulations are currently in clinical trials.…”

“…More importantly, spray-drying can result in uniform particle morphology. 114,149,150 In industry, spray-drying is a continuous production method, scalable for commercial production volumes.…”

Targeting Inhaled Therapy beyond the Lungs

“…Success for examples such as inhaled administration of human growth hormone [4,5,6] and insulin [7,8,9,10,11,12,13] is a strong motivator for exploring this route of drug administration. Inhaled drug delivery can be the answer to increase bioavailability of poorly soluble drugs that have poor absorption and bioavailability in the gastrointestinal tract when orally administered or are highly metabolized by the liver.…”