Development of inhaled powder formulation of antimicrobial agents by spray freeze drying technology

Abstract

In the treatment of respiratory infections, antimicrobial agents are usually administered via oral or parenteral routes. However, systemic administration of antimicrobial agents is often associated with poor lung distribution and systemic toxicity. Inhaled dry powder is an attractive dosage form to deliver antimicrobials for respiratory infections, as it allows the direct application of drug to the site of infection with the capacity of high dose delivery and ease of administration. Currently, there is a limited number of antimicrobial powder formulations available on the market for respiratory infections. The overall aim of this thesis is to develop inhaled powder formulations of antimicrobial agents, particularly for the treatment of lung fungal and viral infections. Spray freeze drying (SFD), a particle engineering technology that typically produces porous particles with good aerosolisation property, was used for powder preparation in this study. The first part of this thesis focuses on the development of dry powder of voriconazole, a first-line antifungal agent, by SFD with mannitol as bulking agent. The factorial design analysis revealed that a high voriconazole content enhanced powder aerosolisation performance as the hydrophobic nature of voriconazole facilitates powder dispersion. Furthermore, a high drying temperature leads to a faster sublimation rate, resulting in the formation of highly porous and brittle particles that are fragmented during dispersion, hence better aerosolisation property. The optimal formulation, which contained 80% (w/w) voriconazole content and was prepared with a high primary drying temperature (−10 ºC), exhibited a fine particle fraction (FPF, fraction of particles with aerodynamic diameter < 5 µm) over 40% in Next Generation Impactor (NGI) study. The dispersion of the optimal formulation by a low-resistance inhaler (Breezhaler®) was flow rate-independent. Desirable biodistribution profile with high drug concentration in the lungs and reduced systemic exposure was demonstrated in mice following pulmonary delivery of voriconazole powder. Future investigation will evaluate the antifungal activity of inhaled voriconazole powder against pulmonary aspergillosis.

In the second part of this thesis, inhaled powder formulation of tamibarotene, a retinoid derivative with broad-spectrum antiviral activity, was developed by SFD. With the presence of hydroxypropyl-β-cyclodextrin (HPBCD) as solubility enhancer at 1:2 tamibarotene: HPBCD molar ratio, the aqueous solubility, dissolution rate, and in vitro antiviral activity of tamibarotene powder was successfully improved. The formulation containing 10% (w/w) tamibarotene, which was prepared with a two-fluid nozzle, presented good aerosol performance with FPF over 60%. Pharmacokinetic study showed rapid drug absorption and high bioavailability in the lungs following intratracheal administration of tamibarotene powder in mice. More importantly, a broad-spectrum antiviral efficacy of inhaled tamibarotene powder against coronaviruses (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] and Middle East respiratory syndrome coronavirus [MERS-CoV]) and influenza A virus (H1N1) was successfully demonstrated in infected mouse and hamster models with decreased viral load and titre. Future work will focus on increasing the drug loading of tamibarotene in the formulation to reduce powder dose required for therapeutic activity.

Collectively, these findings present the great potential of SFD technique in the development of inhalable dry powder formulations of antimicrobial drugs.