Abstract
While the inhalation route has been used for millennia for pharmacologic effect, the biological barriers to treating lung disease created real challenges for the pharmaceutical industry until sophisticated device and formulation technologies emerged over the past fifty years. There are now several inhaled device technologies that enable delivery of therapeutics at high efficiency to the lung and avoid excessive deposition in the oropharyngeal region. Chemistry and formulation technologies have also emerged to prolong retention of drug at the active site by overcoming degradation and clearance mechanisms, or by reducing the rate of systemic absorption. These technologies have also been utilized to improve tolerability or to facilitate uptake within cells when there are intracellular targets. This paper describes the biological barriers and provides recent examples utilizing formulation technologies or drug chemistry modifications to overcome those barriers.
Highlights
Pulmonary delivery of therapeutics is generally accepted as an ideal strategy to deliver an effective amount of drug to the airways to treat diseases including asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) and pulmonary arterial hypertension (PAH), among others [1]
Initial formulation efforts using Treprostinil Palmitil (TP) focused on a solid lipid nanoparticle formulation, called treprostinil palmitil inhalation solution (TPIS) that was delivered via a nebulizer
Pulmonary fibrosis (PF) is a progressive respiratory condition characterized by chronic fibrosis of the lung interstitial tissues that is associated with diminished lung function and a high mortality rate with limited treatment options [109]
Summary
Pulmonary delivery of therapeutics is generally accepted as an ideal strategy to deliver an effective amount of drug to the airways to treat diseases including asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) and pulmonary arterial hypertension (PAH), among others [1]. Many of the early inhaled therapies were repositioned after initially being administered by the oral or injectable routes [2] This change in delivery route was initiated in many cases to avoid systemic side effects and improve targeting to the lung allowing delivery of higher doses that improved efficacy. The inhalation route was not the original choice due to the inconvenience, poor efficiency, variability in delivered dose and lack of portability of the early generation of aerosol delivery technologies [3]. Innovations in inhaler device technologies have addressed the first biological hurdle, which is to minimize oropharyngeal deposition, resulting in a reproducible dose of drug to the lung. The criticality of the reproducibility of lung delivery depends on the drug and the indication Those indications with narrow therapeutic windows may require delivery systems with exceptional control over the emitted dose and how the aerosol is generated and inhaled. We provide examples of how these barriers can be overcome using formulation technologies or modifying the chemistry of the compound
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