ORCID
https://orcid.org/0000-0001-6644-1069
Date of Award
2024
Document Type
Dissertation
Degree Name
Philosophy (Ph.D)
Department
Pharmaceutical Sciences
First Advisor
Nitesh K Kunda
Second Advisor
Bhagwan Rohera
Third Advisor
Tanaji Talele
Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), remains a pressing concern globally. The emergence of drug-resistant strains and the need for prolonged treatment regimens continue to complicate disease management. Innovative therapeutic strategies are urgently required to enhance treatment efficacy, improve patient adherence, and minimize adverse effects. Toward this, strategies involving use of drug combinations, reducing dosing frequencies, and targeting TB-infected cells are gaining attention. In my dissertation, we explored the combination therapy involving two FDA-approved anti-TB drugs, Bedaquiline (BDQ) and Pretomanid (PTD). The BDQ-PTD combination reduced minimum inhibitory concentration (MIC), compared to individual drugs and demonstrated additive/synergistic effects at 1:4 drug ratio. In addition, to improve the drug solubility and enable local delivery into the lungs (via inhalation), the drugs were encapsulated in polymeric nanoparticles (PLGA NPs) and spray-dried into dry powder particles (PLGA NPs SD; non-targeted formulation). Further, to get desired aerosolization properties of spray-dried powder, Quality-by-Design (QbD), a regulatory-based approach was employed. Prior knowledge in spray drying and risk assessment were utilized as part of the QbD approach which helped optimize the spray drying parameters. The optimized non-targeted formulation demonstrated high drug loading, biphasic drug release, long-term storage stability, and suitable aerosolization performance (MMAD 1-5 µm and FPF >75%). Further, the non-targeted formulation demonstrated similar MIC in vitro and enhanced intracellular M.tb inhibition, in infection studies, compared to free drug combination. However, to facilitate active targeting of macrophages wherein TB resides, we prepared mannose-decorated PLGA NPs (Man-PLGA NPs; targeted formulation) using QbD-optimized process parameters The targeted formulation enhanced macrophage targeting via receptor-mediated endocytosis and phagocytosis in vitro and further resulted in bacterial inhibition. Lastly, a TB spheroid model was developed for in vitro screening of non-targeted and targeted formulations. The developed TB spheroid models showed uniform size distribution, high cell viability and lipid deposition, closely mimicking the physiological condition of granulomas in vitro. Targeted formulation demonstrated superior intracellular bacterial inhibition in TB spheroid model compared to free drug combination and non-targeted formulation. In summary, the potential of combination therapy, particulate-based inhaled drug delivery, and active targeting were successfully investigated to advance efficient and patient-friendly TB treatments.
Recommended Citation
Patil, Suyash M., "A QUALITY-BY-DESIGN APPROACH FOR THE DEVELOPMENT OF INHALABLE DRY POWDERS FOR TUBERCULOSIS (TB) TREATMENT" (2024). Theses and Dissertations. 818.
https://scholar.stjohns.edu/theses_dissertations/818