Co-Delivery of D-LAK Antimicrobial Peptide and Capreomycin as Inhaled Powder Formulation to Combat Drug-Resistant Tuberculosis

Abstract

Introduction The emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) posed a severe challenge to tuberculosis (TB) management. The treatment of MDR-TB involves second-line anti-TB agents, most of which are injectable and highly toxic. Previous metabolomics study of the Mtb membrane revealed that two antimicrobial peptides, D-LAK120-A and D-LAK120-HP13, can potentiate the efficacy of capreomycin against mycobacteria. Aims As both capreomycin and peptides are not orally available, this study aimed to formulate combined formulations of capreomycin and D-LAK peptides as inhalable dry powder by spray drying. Methods and Results A total of 16 formulations were prepared with different levels of drug content and capreomycin to peptide ratios. A good production yield of over 60% (w/w) was achieved in most formulations. The co-spray dried particles exhibited spherical shape with a smooth surface and contained low residual moisture of below 2%. Both capreomycin and D-LAK peptides were enriched at the surface of the particles. The aerosol performance of the formulations was evaluated with Next Generation Impactor (NGI) coupled with Breezhaler®. While no significant difference was observed in terms of emitted fraction (EF) and fine particle fraction (FPF) among the different formulations, lowering the flow rate from 90 L/min to 60 L/min could reduce the impaction at the throat and improve the FPF to over 50%. Conclusions Overall, this study showed the feasibility of producing co-spray dried formulation of capreomycin and antimicrobial peptides for pulmonary delivery. Future study on their antibacterial effect is warranted.

Accessing Properties of Molecular Compounds Involved in Cellular Metabolic Processes with Electron Paramagnetic Resonance, Raman Spectroscopy, and Differential Scanning Calorimetry

“…Another variant of the lipid-based encapsulation of antibiotics (including the "classic" first-line drug isoniazid) was proposed in the work [169]; the DSC provided an opportunity to characterise the optimised compatibility of drug and lipids in the composition. The specific form of drug delivery in the form of co-spray-dried powders comprised of the different compositions of capreomycin (a semisynthetic antibiotic) and antimicrobial peptides (i.e., biomolecules) for pulmonary delivery was characterised with DSC in the work [170].…”

Advances in Pulmonary Drug Delivery Systems and Inhalation Formulations

“…Antimicrobial peptides have emerged to be promising candidate to combat MDR-TB. Lam et al [4] report the development of inhaled powder formulations containing synergistic combinations of capreomycin and D-LAK antimicrobial peptides as potential new therapy against MDR-TB. This study provides insights on the development of inhaled antimicrobial peptides against respiratory infections.…”