Development of dual targeting powder formulations for inhalation delivery to both the upper and lower airways

Abstract

Conventional respiratory drug delivery methods typically include either pulmonary delivery via oral inhalation, which bypasses the nasal cavity, or intranasal delivery to target the nasal cavity with minimized lung deposition. This thesis explores a novel dual targeting approach that can effectively deliver drugs simultaneously to both the upper and lower respiratory tract by nasal inhalation. Spray drying (SD) and spray freeze drying (SFD) were used to produce powders with distinct particle size ranges for nasal and lung deposition. By blending these powders in specific proportions, the dual targeting powder achieved bimodal size distribution, allowing precise control over the aerosol deposition fractions.

The dual targeting approach offers diverse clinical applications, with this thesis focusing on respiratory viral infections, a major global health challenge. Viral infections begin in the upper airways and can progress to the lungs, causing severe pneumonia and respiratory distress. While existing antiviral therapies face limitations, including poor lung distribution and drug resistance, a dual targeting strategy can deliver a broad-spectrum antiviral directly to infection sites for early treatment and prophylaxis during unpredictable viral outbreaks, such as the Coronavirus Disease 2019 (COVID-19) pandemic.

The dual targeting strategy was tested using broad-spectrum antiviral agents, including the repurposed drug tamibarotene and the neutralizing monoclonal antibody WKS13. Utilizing factorial design, an optimized SFD nasal formulation of tamibarotene was developed. Dual targeting powder formulations of tamibarotene were produced by SFD and SD. The powder blends exhibited bimodal size distribution with controllable aerosol deposition profile and enhanced dissolution rate. The dual targeting formulation method using SD was preferred over SFD due to the wider range of nasal fraction (NF, 55% to 85%) and fine particle fraction (FPF, 11% to 38%), less flow rate dependent aerosol performance, and greater industrial scalability. Dual targeting powders of WKS13 produced using SD showed preservation of antiviral activity and antibody structural integrity, and customisable aerosol deposition profile. In vivo studies demonstrated that dual administration of WKS13 powders to both the nasal cavity and lungs of hamsters provided prophylactic protection against SARS-CoV-2 Delta variant, and reduced transmissibility.

Building upon the proof-of-concept antiviral studies, the research further explored the incorporation of stabilizing salts in dual targeting mannitol powders to pave the way for future human scintigraphy studies. The presence of stabilizing salts increased residual moisture and decreased FPF. Aerosol characterization using a glass expansion chamber coupled with the Next Generation Impactor (NGI) showed a NF:FPF of 58:41, and demonstrated controllable aerosol deposition profile that varied linearly with the mixing ratio. Assessment with a 3D-printed nasal replica coupled to the NGI revealed that the actual nasal deposition was higher, with a NF:FPF of 68:24. Multiple dispersions with reduced powder load enhanced powder dispersion and improved the FPF of the dual targeting formulations.

The findings from this work have the potential to transform the landscape of respiratory disease management, offering a promising solution to enhance the delivery and efficacy of therapeutic agents. Future work should focus on increasing lung deposition, exploring therapeutic applications, and conducting clinical trials to validate its safety and efficacy.