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

Durairaj Thiyagarajan,Karen F W Besecke,Birgit Nothdurft,Constantin Hozsa,Benedikt Huck,Claus Feldmann,David Rudolph,Mark Rutschmann,Marcus Koch,Claus-Michael Lehr,Marcus Furch,Brigitta Loretz,Robert K Gieseler

doi:10.1007/s13346-021-01011-7

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

Highlights

Respiratory infections and multi‐drug resistanceThe mortality rate associated with microbial infections increases exponentially with the rate of antibiotic resistance, which calls for advanced therapeutic strategies to eradicate drug-resistant pathogens [1]
Potent new antibiotics like benzothiazinone 043 (BTZ), delamanid, pretomanid, and bedaquiline were developed against M. tuberculosis, while some of the classical antibiotics such as levofloxacin (LVX) and rifampicin are still used in the clinic [8]
We found that the formation of MPs by spray drying of lactose was improved by employing the hydrophobic amino acid, leucine

Summary

Introduction

Respiratory infections and multi‐drug resistanceThe mortality rate associated with microbial infections increases exponentially with the rate of antibiotic resistance, which calls for advanced therapeutic strategies to eradicate drug-resistant pathogens [1]. Mycobacterium tuberculosis (M. tuberculosis) is a serious healthcare issue due to the development of multi-drug resistance and difficulties in its complete eradication leading to high mortality [2,3,4,5]. In contrast to systemically administered drugs, novel therapeutic strategies taking advantage of local pulmonary delivery of nanomedical formulations to the site of infection hold promise to overcome mycobacterial respiratory tract infections [2, 3]. Mycobacterial infections such as with M. tuberculosis have been a long-standing healthcare issue requiring highly potent medications [6, 7]. Ensuring sufficient delivery of these antibiotics to the site of infection is critical due to the drugs’ limited solubilities and unfavorable pharmacokinetic properties [9]

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Discussion

Conclusion