Excipient-free inhalable combination shell-core microparticles with clofazimine as shell for extended pulmonary retention of isoniazid in core

Abstract

Pulmonary delivery of combination anti-tubercular drugs can prevent emergence of drug resistance and improve therapeutic efficacy. However, several drugs in anti-Tuberculosis combinations possess contrasting physicochemical properties that necessitate precise particle engineering with meticulous design for successful co-delivery. High dose requirements further constrain addition of excipients in the formulation. In this work, a clofazimine shell − isoniazid core combination, excipient-free dry powder inhalable microparticle formulation (CFZ INH DPMs) is designed to extend release and prolong pulmonary retention of the short-half-life INH. Firstly, INH-acetone incompatibility was resolved by employing 3 fluid-nozzle spray drying as conventional spray drying of pure INH yielded large particle sizes (D₅₀-26.64 µm) and poor yield for CFZ, whereas CFZ INH DPMs formulation exhibited desired aerodynamic size (D₅₀-3.04 µm; 3.36 µm for INH and 3.28 µm for CFZ). Shell-core morphology was confirmed using TEM and confocal microscopy. DSC and XRD revealed CFZ and INH existed in their inherent crystalline form in CFZ INH DPMs. Solubility of CFZ from the combination DPMs in simulated lung fluid was improved 2 times compared to pure CFZ, while INH dissolution was retarded (85 % in 4 h). The interfacial behavior of DPPC with CFZ using Langmuir-Blodgett isotherms revealed interactions that explain improved solubility of CFZ in pulmonary lipids. In a RAW macrophage culture study, cellular internalization of prepared formulation within 4 h was observed whereas intratracheal administration to Wistar rats demonstrated retention of INH in lungs upto 4 h compared to clearance of pure INH within 1 h. In summation, CFZ INH DPMs demonstrate promising potential for pulmonary targeting and retention of combination anti-TB drugs.