Several studies have stated that mucus is a critical hurdle for drug delivery to the mucosal tissues. As a result, Polymeric nanoparticles that can overcome mucus barriers are gaining popularity for controlled drug delivery into intra-macrophages to attain high intracellular drug concentration. The present study was aimed to fabricate inhalable N-acetylcysteine (NAC) modified PLGA mucus penetrating particles using the double emulsion method (w/o/w) for target delivery to alveolar macrophages and minimize the dose-related adverse effects, efficiently encapsulate hydrophilic drug, sustain the release profile and prolong the retention time for the management of tuberculosis. Among the numerous formulations, the drug/polymer ratio of 1:10 with 0.50% PVA concentration and sonication time for 2 min s was chosen for further research. The formulated nanoparticles had a mean particle size of 307.50 ± 9.54 nm, PDI was 0.136 ± 0.02, zeta potential about −11.3 ± 0.4 mV, decent entrapment efficiency (55.46 ± 2.40%), drug loading (9.05 ± 0.22%), and excellent flowability. FTIR confirmed that NAC and PLGA were compatible with each other. SEM graphs elucidated that the nanoparticles were spherically shaped with a slightly rough surface whereas TEM analysis ensured the nanometer size nanoparticles and coating of lipid over NPs surface. PXRD spectrum concluded the transformation of the drug from crystalline to amorphous state in the formulation.
In vitro
release pattern was biphasic started with burst release (64.67 ± 1.53% within 12hrs) followed by sustained release over 48hrs thus enabling the prolonged replenishing of NAC.
In vitro
lung deposition study pronounced that coated NAC-PLGA-MPPs showed favorable results in terms of emitted dose (86.67 ± 2.52%), MMAD value (2.57 ± 0.12 μm), GSD value (1.55 ± 0.11 μm), and FPF of 62.67 ± 2.08% for the deposition and targeting the lungs. Finally,
in vitro
efficacy studies demonstrated that NAC-PLGA-MPPs presented more prominent antibacterial activity against
MTB
H37Rv strain as compared to NAC. Hence, PLGA based particles could be a better strategy to deliver the NAC for lung targeting.
N-Acetylcysteine (NAC) is a precursor of Glutathione (GSH) which possess an immense potential of mucolytic, anti-inflammatory and antioxidant properties against several diseases including tuberculosis. Since last several decades, NAC is being primarily used to treat lung conditions as well as paracetamol-induced liver toxicity However, NAC exhibited potential antimycobacterial activity through several mechanism including immunomodulation, enhancement of GSH level, and by direct antimycobacterial effect. Herein, we synthesized and characterized lactose coated N-acetylcysteine loaded PLGA composites (NAC-PLGA@Cs) by double emulsion solvent evaporation technique. The physicochemical characterization studies revealed the compatibility of the drug with excipients. Moreover, NAC-PLGA@Cs showed particle size with 310 ± 5.5nm, PDI with 0.15 ± 0.1, and zeta potential with − 11.5 ± 0.4 mV. In vitro release study suggested the biphasic release profile. Likewise, in vitro lung deposition studies revealed remarkable lung deposition parameters, indicating effective particles size for efficient pulmonary delivery. Additionally, in vitro study for antimycobacterial activity exhibited superior antibacterial activity against MTB H37Rv. Subsequently, we hypothesized that NAC incorporated PLGA composites could be a novel approach in the battle of fighting for pulmonary tuberculosis.
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