Track: Formulation and Delivery - Chemical - Formulation - Inhalation and Nasal
Category: Poster Abstract
Expanding Global Tuberculosis Treatment Through a Novel Inhaled Clofazimine Product
Purpose: Tuberculosis (TB) is the leading cause of death globally with 10 million new cases of TB and 1.3 million deaths as per annual report. Current treatment approaches are complicated by increasing rates of antibiotic resistance, long treatment durations, high pill burdens, and social and economic disparities across the world. Recent studies advocate oral clofazimine (CFZ) as a viable treatment option, especially against drug resistant TB. However, oral CFZ’s clinical use is limited by poor pharmacokinetic properties and serious adverse effects. An inhaled CFZ formulation could better target the site of TB infection, expand treatment options, and reduce systemic adverse effects. Targeting CFZ to the lungs presents several formulation and delivery challenges to the pharmaceutical scientist. Recent publications by Verma et.al. (2013), Brunaugh et.al. (2017), and Banaschewski et al. (2019) describe various approaches to inhaled CFZ formulations and delivery. These articles suggest inhaled CFZ can produce drug concentrations in lung tissue sufficiently high to kill TB, be taken up by alveolar macrophages, and significantly reduce the TB burden in a mouse model of TB. However, dose uncertainty as well as methodological ambiguity between the articles prevents prediction of pharmacokinetic changes for inhaled CFZ. A separate inhaled CFZ dry powder formulation has been developed by the Tolman Lab with favorable properties for inhalation to the deep lung. This formulation consists of a spray dried CFZ powder with dipalmitoylphosphatidylcholine (DPPC) containing 83.2 ± 2.0 % of drug between the size range of 1.82 - 4.74 μm. Incorporation of DPPC (a natural lung surfactant) improves the aerodynamic properties of the formulation and increases the CFZ solubility and could contribute to improved anti-tubercular activity compared to CFZ alone. This poster addresses the challenges associated with dose determination of an inhaled CFZ formulation in preparation for the pharmacokinetic analysis of inhaled CFZ. A pilot study was conducted to quantify the inhaled CFZ dose in healthy mice. Preliminary results from that pilot study is also included and compared with published studies. Methods: The optimized CFZ-DPPC dry powder inhalation formulation was prepared by spray drying and characterized. This inhaled CFZ-DPPC formulation was inhaled by healthy male Balb/c mice using a custom designed nose-only inhalation dosing apparatus using various experimental parameters in an attempt to replicate the dosing described by Verma et.al. (2013). The animals were immediately euthanized by CO2 narcosis followed by blood collection by cardiac puncture and necroptic organ collection. Organs and plasma samples separated from whole blood were flash frozen and stored at -80°C. CFZ concentration in plasma and organ samples was determined by a liquid-liquid organic phase extraction followed by LC-MS analysis with an internal standard. Results: The inhaled CFZ doses in mice were 15.23 ± 12.67 μg and 10.58 ± 2.93 μg for two different sets of dosing parameters. These inhaled CFZ masses correspond to lung tissue concentrations of 61.36 ± 50.72 μg/g wet lung and 46.79 ± 9.69 μg/g wet lung. These CFZ concentrations align with those reported by Banaschewski et al. (2019) but for vastly different dosing regiments and suggest a single inhaled CFZ-DPPC dose can produce equivalent concentrations compared to chronic dosing with an inhaled CFZ suspension. However, these findings conflict with the reported doses achieved by Verma et.al. (2013) and suggest underlying methodological inconsistencies. Additionally, CFZ’s physicochemical properties directly affect the measured inhaled CFZ dose and lung concentrations as suggested by the findings from Eixarch et.al. (2010). Conclusion: An inhaled CFZ-DPPC dry powder formulation has the potential to expand TB treatment options. Specifically, it is anticipated that high CFZ concentrations will be retained in the lung tissue for extended periods of time to provide prolonged and sustained anti-TB activity while reducing systemic CFZ exposure. These advantages could be used in combination with current treatment approaches to improve outcomes against the global TB endemic. The enhanced CFZ content in the lung will aid the global health missions of WHO and NIAID for a targeted 90 % reduction in world TB deaths by the end of 2030.
References: Banaschewski, B., et.al. (2019). Clofazimine inhalation suspension for the aerosol treatment of pulmonary nontuberculous mycobacterial infections. Journal of Cystic Fibrosis, 18(5), 714-720. Brunaugh, A. D., et.al. (2017). Excipient-free pulmonary delivery and macrophage targeting of clofazimine via air jet micronization. Molecular pharmaceutics, 14(11), 4019-4031. Verma, R. K., et.al. (2013). Inhaled microparticles containing clofazimine are efficacious in treatment of experimental tuberculosis in mice. Antimicrobial agents and chemotherapy, 57(2), 1050-1052. Eixarch, H., et.al. (2010). Drug delivery to the lung: permeability and physicochemical characteristics of drugs as the basis for a pulmonary biopharmaceutical classification system (pBCS). Journal of Epithelial Biology & Pharmacology, 3(1), 1-14.