Will pulmonary drug delivery for systemic application ever fulfill its rich promise?

While oral delivery of tablets and capsules remains the preferred treatment modality for most patients, inhaled therapeutics have dominated the landscape for managing many common lung diseases including asthma and chronic obstructive pulmonary disease and orphan lung diseases like cystic fibrosis (CF) and pulmonary hypertension [1]. The inhalation route allows drugs to be delivered directly to the site of disease, leading to improved efficacy, and reduces the potential for side effects due to lower systemic exposure [1]. These inhaled treatments are available in a variety of formats, including jet and mesh nebulizers, soft-mist inhalers, metered dose inhalers (MDIs), and dry powder inhalers (DPIs), and new technologies are becoming available to improve convenience and adherence, e.g. breath-actuation, electronic monitoring, and feedback [1]. The potential to use the inhalation route to treat systemic disease has long been debated, especially with the emergence of biotechnology products [1]. The application of recombinant DNA technology to produce biopharmaceuticals, and the subsequent approval of recombinant human insulin in 1982, ushered in the era of biotechnology. The initial focus on peptides for hormone replacement rapidly expanded to large-molecular-weight proteins and antibodies, as understanding of the fermentation, cell culture, and purification sciences improved. Biologics for systemic application could not be given orally due to degradation in the gastrointestinal tract and so have relied upon injection or infusion for efficacy. For as long as these products have been on the market, scientists have sought innovative technologies to overcome the discomfort and stigma associated with injections, the ‘crude’ insertion of metal shafts into the body to allow proteins access to the subcutaneous (SC) tissue [1]. Noninvasive administration of biologics remains an elusive goal with the exception of the inhalation route: the lung with its large surface area and the thin, alveolar epithelium makes such delivery possible and this attracted intense focus from the early 1990s. Early clinical success spurred optimism that the lung could be utilized for systemic uptake of insulin and other biologics [2]. Inhaled products were conceived to replace injections for diseases as diverse as diabetes (insulin and GLP-1), osteoporosis (parathyroid hormone), growth hormone (GH) deficiency, anemia (erythropoietin), hepatitis (interferon alpha [IFNα]), multiple sclerosis (interferon beta [IFNβ]), pain management (morphine and fentanyl), migraines (triptans and dihydroergotamine), and anxiety disorder (loxapine) [1,2]. However, significant technical hurdles had to be overcome to develop formulations that possessed adequate stability, ideally at room temperature for convenience, and inhalation systems that were efficient, reproducible, and simple to use correctly. Interestingly, safety concerns about delivery of proteins to the lung were much reduced after the approval of the first protein delivered by inhalation – recombinant human DNase – for the treatment of CF [1]. However, while conception occurred for many of these products more than two decades ago, few have reached the market and none has achieved commercial success.