Design Considerations for Intratracheal Delivery Devices to Achieve Proof-of-Concept Dry Powder Biopharmaceutical Delivery in Mice

Abstract

Purpose Intratracheal delivery and consistent dosing of dry powder vaccines is especially challenging in mice. To address this issue, device design of positive pressure dosators and actuation parameters were assessed for their impacts on powder flowability and in vivo dry powder delivery. Methods A chamber-loading dosator assembled with stainless-steel, polypropylene or polytetrafluoroethylene needle-tips was used to determine optimal actuation parameters. Powder loading methods including tamp-loading, chamber-loading and pipette tip-loading were compared to assess performance of the dosator delivery device in mice. Results Available dose was highest (45%) with a stainless-steel tip loaded with an optimal mass and syringe air volume, primarily due to the ability of this configuration to dissipate static charge. However, this tip encouraged more agglomeration along its flow path in the presence of humidity and was too rigid for intubation of mice compared to a more flexible polypropylene tip. Using optimized actuation parameters, the polypropylene pipette tip-loading dosator achieved an acceptable in vivo emitted dose of 50% in mice. After administering two doses of a spray dried adenovirus encapsulated in mannitol-dextran, high bioactivity was observed in excised mouse lung tissue three days post-infection. Conclusions This proof-of-concept study demonstrates for the first time that intratracheal delivery of a thermally stable, viral-vectored dry powder can achieve equivalent bioactivity to the same powder, reconstituted and delivered intratracheally. This work may guide the design and device selection process for murine intratracheal delivery of dry powder vaccines to help progress this promising area of inhalable therapeutics.

Performance Testing of a Homemade Aerosol Generator for Pulmonary Administration of Dry Powder Formulations to Mice

“…Also, to ensure delivery while using such a low amount of air and to enhance the powder dispersion process with the Penn-Century Insufflator, a high air velocity is required, which additionally contributes to poor deposition in the lungs because of inertial impaction to the walls of the upper respiratory tract [ 4 , 10 , 11 ]. Higher air volumes, up to 900 µL, have been used to increase the dispersion and amount of powder delivered [ 12 ], though this is even higher than the total lung capacity of mice (approximately 750 µL). Such high volumes are known to cause serious tissue damage in the lungs of mice.…”

“…Over the years, various custom-made systems have been developed, often consisting of a small powder reservoir, a syringe and a needle only [ 12 , 14 , 15 ]. These systems, however, all have in common with the Penn-Century Insufflator the fact that they combine dispersion and administration in a single step.…”

Advances in Pulmonary Drug Delivery Systems and Inhalation Formulations

“…However, in vivo dry powder administration is challenging in murine models. To address this problem, Thompson et al [9] developed different custom-made dosator designs for intratracheal dry powder delivery in mouse and their performance was compared. This study offers practical guidance on strategies to improve intratracheal delivery of dry powder formulation for use in animal studies.…”