Development of a proliposomal pretomanid dry powder inhaler as a novel alternative approach for combating pulmonary tuberculosis

Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) continue as public health concerns. Inhaled drug therapy for TB has substantial benefits in combating the causal agent of TB (Mycobacterium tuberculosis). Pretomanid is a promising candidate in an optional combined regimen for XDR-TB. Pretomanid has demonstrated high potency against M. tuberculosis in both the active and latent phases. Conventional spray drying was used to formulate pretomanid as dry powder inhalers (DPIs) for deep lung delivery using a proliposomal system with a trehalose coarse excipient to enhance the drug solubility.

Highlights

The proliposomal PTM for DPIs was successfully produced through spray drying.

The selected formulations were inhalable powders with suitable physicochemical properties.

Proliposomal PTM for DPIs significantly improved drug dissolution and permeation.

The formulations exhibited superior antimicrobial activity and were safe for respiratory cell lines.

Co-spray drying with L-leucine protected hygroscopic trehalose in formulations and improved powder aerosolization. Higher amounts of L-leucine (40–50 % w/w) resulted in the formation of mesoporous particles with high percentages of drug content and entrapment efficiency. The aerosolized powders demonstrated both geometric and median aerodynamic diameters < 5 µm with > 90 % emitted dose and > 50 % fine particle fraction. Upon reconstitution in simulated physiological fluid, the proliposomes completely converted to liposomes, exhibiting suitable particle sizes (130–300 nm) with stable colloids and improving drug solubility, leading to higher drug dissolution compared to the drug alone. Inhalable pretomanid showed higher antimycobacterial activity than pretomanid alone. The formulations were safe for all broncho-epithelial cell lines and alveolar macrophages, thus indicating their potential suitability for DPIs targeting pulmonary TB.

Chemicals and Reagents

PTM (purity 99 %, molecular weight 359.26 g/mol), cholesterol from lanolin, D-(+)-trehalose dihydrate, and L-leucine were purchased from MedChemExpress LLC. USA, Fluka Chemika Switzerland, Fluka Biochemika Germany, and Ajinomoto Co., Inc., Japan, respectively. Phospholipon® 90G (unsaturated phosphatidylcholine) was kindly gifted from Lipoid, Germany. All solvents in this study were of high-performance liquid chromatography (HPLC) grade (Merck, Germany).

Nattanit Aekwattanaphol, Shyamal C. Das, Prakash Khadka, Titpawan Nakpheng, Muhammad Ali Khumaini Mudhar Bintang, Teerapol Srichana, Development of a proliposomal pretomanid dry powder inhaler as a novel alternative approach for combating pulmonary tuberculosis, International Journal of Pharmaceutics, 2024, 124608, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124608.