Challenges Associated with the Pulmonary Delivery of Therapeutic Dry Powders for Preclinical Testing

Abstract

Significant progress has been made over the last half-century in delivering therapeutics by the pulmonary route. Inhaled therapeutics are administered to humans using metered-dose inhalers, nebulizers, or dry powder inhalers, and each device requires a different formulation strategy for the therapeutic to be successfully delivered into the lung. In recent years, there has been a shift to the use of dry powder inhalers due to advantages in the consistency of the dose delivered, ease of administration, and formulation stability. Numerous preclinical studies, involving small and large animals, have evaluated dry powder drugs, vaccines, and immunotherapeutics delivered by the pulmonary route. These studies used different dry powder delivery devices including nose-only, whole-body, and intratracheal administration systems, each of which works with different aerosolization mechanisms. Unfortunately, these delivery platforms usually lead to variable powder deposition in the respiratory tract of animals. In this review, we will discuss obstacles and variables that affect successful pulmonary delivery and uniform powder deposition in the respiratory tract, such as the type of delivery device, dry powder formulation, and the animal model used. We will conclude by outlining factors that enhance the reproducible deposition of dry powders in the respiratory tract of preclinical animal models and identifying knowledge and technology gaps within the field. We will also outline the important factors necessary for successful translation of studies performed in preclinical models to humans.

Respiratory Tract Deposition and Distribution Pattern of Microparticles in Mice Using Different Pulmonary Delivery Techniques

“…One of the reasons for the poor clinical translation is the lack of effective pulmonary delivery tools for preclinical studies. Further, a lack of standardized and effective inhalation devices for preclinical use has resulted in poor reproducibility between laboratories and is a huge impediment in the successful translation of pulmonary formulations to humans [ 20 ]. Here, we successfully evaluated three commonly used preclinical pulmonary devices/techniques in mice with respect to respiratory tract deposition and distribution patterns using IVIS imaging.…”

“…Further, Chakravarthy et al have used the aspiration technique to deliver formulations to the lungs and target the alveolar macrophages [ 35 ]. All these preclinical studies demonstrate the use of preclinical pulmonary delivery devices to be arbitrary, with variable results achieved [ 20 ].…”

“…Unfortunately, many of the pulmonary drug and vaccine candidates that are successfully evaluated in preclinical studies do not proceed to clinical trials; the failure to translate preclinical studies into humans is despite a plethora of preclinical studies employing the pulmonary route for therapeutics and vaccine delivery [ 15 , 16 , 17 , 18 , 19 ]. This problem was recently discussed by Muttil and colleagues [ 20 ], who suggested that one of the reasons for poor translation of preclinical studies is due to the different mechanisms by which preclinical inhalation devices operate compared to human inhalers. This prompted us to compare the three commonly used preclinical inhalation devices/techniques to provide a better understanding of the literature that employs these devices.…”

“…Current preclinical devices for pulmonary administration either employ passive or direct inhalation techniques. Direct inhalation techniques include intratracheal (IT) and intranasal instillation, and tracheostomy [ 20 ]. IT instillation offers the advantage of precise dosing of the test agent as compared to passive inhalation techniques, as the therapeutic is placed directly into the upper airway [ 21 ].…”

“…Additionally, selection of an appropriate animal model is vital to examine the fate of the inhaled drug. Price et al recently discussed in detail the importance of animal model selection when evaluating an inhaled product in the preclinical stage [ 20 ]. Most of the published papers evaluating inhaled drugs employ small animal models such as mice and rats due to ease of availability, affordability, and handling [ 3 , 7 , 22 , 23 , 24 ].…”