Spray-dried lactose-leucine microparticles for pulmonary delivery of antimycobacterial nanopharmaceuticals

Abstract

Pulmonary delivery of nanocarriers for novel antimycobacterial compounds is challenging because the aerodynamic properties of nanomaterials are sub-optimal for such purposes. Here, we report the development of dry powder formulations for nanocarriers containing benzothiazinone 043 (BTZ) or levofloxacin (LVX), respectively. The intricacy is to generate dry powder aerosols with adequate aerodynamic properties while maintaining both nanostructural integrity and compound activity until reaching the deeper lung compartments. Microparticles (MPs) were prepared using vibrating mesh spray drying with lactose and leucine as approved excipients for oral inhalation drug products. MP morphologies and sizes were measured using various biophysical techniques including determination of geometric and aerodynamic mean sizes, X-ray diffraction, and confocal and focused ion beam scanning electron microscopy. Differences in the nanocarriers’ characteristics influenced the MPs’ sizes and shapes, their aerodynamic properties, and, hence, also the fraction available for lung deposition. Spay-dried powders of a BTZ nanosuspension, BTZ-loaded silica nanoparticles (NPs), and LVX-loaded liposomes showed promising respirable fractions, in contrast to zirconyl hydrogen phosphate nanocontainers. While the colloidal stability of silica NPs was improved after spray drying, MPs encapsulating either BTZ nanosuspensions or LVX-loaded liposomes showed the highest respirable fractions and active pharmaceutical ingredient loads. Importantly, for the BTZ nanosuspension, biocompatibility and in vitro uptake by a macrophage model cell line were improved even further after spray drying. Graphical abstract

Optimizing the design and dosing of dry powder inhaler formulations of the cationic liposome adjuvant CAF®01 for pulmonary immunization

“…The DPI formulations of CAF®01-T/D (30:70) prepared with leucine displayed non-significantly higher size and PDI with increasing concentrations of leucine. Prior studies have reported an increased particle size of liposomes after spray drying with L-leucine and lactose (Mangal et al, 2015;Thiyagarajan et al, 2021) due to aggregation in the dissolved microparticle samples (Thiyagarajan et al, 2021). In our recent study with DPI formulations of lipid-polymer hybrid nanoparticles spray-dried with a combination of trehalose, dextran and leucine, we also observed a slight increase in the particle size of nanoparticles after spray drying (Xu et al, 2022a).…”

Nano‐in‐Microparticles for Aerosol Delivery of Antibiotic‐Loaded, Fucose‐Derivatized, and Macrophage‐Targeted Liposomes to Combat Mycobacterial Infections: In Vitro Deposition, Pulmonary Barrier Interactions, and Targeted Delivery

“…Lactose and leucine were selected as well‐established excipients for dry‐powder formulations. [ 26 ] When the concentrations of lactose and leucine were optimized to 2.5% or 1% w/v, respectively, stable microparticles with a high fine‐particle fraction were achieved. To determine its aerodynamic properties after adding BDQ‐loaded liposomes, the microparticles were investigated using a next‐generation impactor.…”

Liposomes techniques of aerosolization for the treatment of obstructive, restrictive and infectious pulmonary diseases: a review

“…Ter domínio das técnicas de aerolização dos lipossomas é importante para garantir um produto com qualidade segundo as especificações (Ran, et al, 2015), uma vez que através destas técnicas é possível preservar a integridade do nanocarreador e minimizar as interações físico-químicas que causam a agregação das partículas (Thiyagarajan, et al, 2021). As técnicas de aerolização mais utilizadas são Spray Drying, Spray Freeze Drying e Freeze Drying (Misra, et al,2009).…”