Treatment Challenges and Need for a New Approach: The traditional treatment regimen for TB involves a lengthy course of 6-12 months, comprising first-line drugs (isoniazid, rifampicin, pyrazinamide, and ethambutol) and second-line drugs (ofloxacin, amikacin, ciprofloxacin, etc.) administered orally or intravenously (Jnawali et al., 2013). Despite the effectiveness of these first- and second-line drugs, the adverse systemic side effects, the high pill count, and the extended duration of therapy often lead to poor patient compliance. Moreover, overuse and misuse of antibiotics have contributed to the emergence of drug-resistant M.tb strains (Allué-Guardia et al., 2021). New treatment approaches focusing on three key aspects – combining drugs effectively to reduce resistance, effective drug delivery systems, and enhancing local drug administration to minimize side effects, are urgently needed. These efforts are crucial for controlling TB’s spread and ultimately eradicating it.
Our Combinatorial Approach – Targeting TB locally via Inhalation: We investigated the formulation of a combination of bedaquiline (BDQ) and pretomanid (PTD) (BPa) drugs co-loaded into polymeric nanoparticles (BPa PLGA NPs) and administered as BPa PLGA NPs spray-dried (BPaD) powder for inhalation (Figure 1) (Patil et al., 2024). The rationale behind this approach is to utilize combination anti-TB therapy to prevent the development of drug resistance while delivering the drugs through inhalation to maximize lung drug deposition and enhance patient compliance by minimizing systemic exposure and associated toxicities.
Additive/Synergistic Combination: Firstly, we used the resazurin microtiter assay (REMA) to confirm that the BDQ-PTD combination showed a four-fold reduction in minimum inhibitory concentration (MIC) compared to individual drugs. Next, based on the MIC values, the calculated fractional inhibitory combination index (FICI), a measure of drug combination effect, was 0.5 for 1:4 BDQ:PTD mass ratio, which is the borderline score for the synergy-additive effect. This FIC Index confirms an increase in the inhibitory activity of the BDQ and PTD from the additive/synergistic effect of the combination owing to a complementary mechanism of action of drugs.
Polymeric Nanoparticles: Next, the drug combination has poor aqueous solubility, limiting the efficient delivery to the target site. Nanocarriers have been widely investigated for solubility enhancement, and polymeric nanoparticles (NPs) offer high drug loading, sustained or controlled drug release, target specificity by surface modification and safety and biocompatibility for human use. We successfully encapsulated the drug combination in Poly(D, L-lactide-co-glycolide) (PLGA) nanocarriers (BPa PLGA NPs), which showed optimum particle properties (size 200 ± 17 nm and surface charge (-) 30 ± 3 mV), high encapsulation efficiency (>80% w/w), and sustained drug release patterns (release over 6 days).
Dry powder preparation: There is interest in local administration using dry powder inhalers (DPIs) of antibiotics to increase local drug deposition, as the lungs are the primary organ of M.tb infection. The successful delivery of the inhaled dose depends on powder properties and compatibility with the inhalation device. Consistency and predictability of the delivered dose are vital, and existing literature demonstrates the intricate interplay of powder and device factors influencing aerosolization performance. This complexity necessitates a Quality-by-Design (QbD) approach for developing and manufacturing new DPI products.
Process Optimization by QbD: QbD is a modern, regulatory-based quality management system that emphasizes the design phase of developing new pharmaceutical products. Risk assessment (RA) unveiled aerosolization performance, nanoparticle size, drug loading, moisture content, and dry powder yield as pivotal quality influencers. Moreover, DoE analysis using Box-Behnken Design, a three-factorial and three-level design, helped optimize critical process parameters of the spray dryer – inlet temperature, aspirator, and feed rate, to achieve the target product profile. The developed dry powder exhibited favorable inhalation delivery characteristics following detailed optimization, including appropriate dry powder particle size (3 – 5 µm), high drug content (10% w/w), efficient aerosolization (aerodynamic diameter (MMAD) 2.27 ± 0.16 µm and fine particle fraction (FPF) >85% w/w), and long-term storage stability (estimated shelf life 18-24 months). Also, findings highlighted the potential of the BDQ-PTD combination in inhibiting extracellular and intracellular M.tb and making a case for a promising TB therapeutic.
Figure 1: A schematic showing our combinatorial approach to deliver bedaquiline and pretomanid-loaded nanoparticles as an inhalable dry powder for the treatment of TB.
Overview and Future Perspective: Our proposed approach involves co-loading the BDQ-PTD drug combination into polymeric nanoparticles and delivering them as a dry inhalable powder. The future for inhaled antibiotic delivery appears promising and is anticipated to expand with advancements in particle engineering and preparation techniques, coupled with the development of improved and patient-friendly inhaler devices. The significant challenges, such as pulmonary toxicity, a restricted range of approved excipients for inhalation use, and the deposition of drugs in diseased lungs, need to be addressed to facilitate the successful translation of inhaled therapeutics into clinical applications (Braunstein et al., 2019). This study contributes scientifically to the EndTB Strategy of WHO, focusing on ending the global TB epidemic with a dramatic decline in TB deaths and cases and eliminating the economic and social burden of TB by 2030 because TB anywhere is TB everywhere (“The End TB Strategy,” 2024).
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