Continuously producible aztreonam-loaded inhalable lipid nanoparticles for cystic fibrosis-associated Pseudomonas aeruginosa infections - Development and in-vitro characterization.

Cystic fibrosis (CF) is a genetic disorder affecting nearly 105,000 patients worldwide and is characterized by poor respiratory function due to accumulation of thick mucus in the lungs, which not just acts as a physical barrier, but also provides a breeding ground for bacterial infections. These infections can be controlled with the help of antibiotics which can be delivered directly into the lungs for amplifying the local anti-bacterial effect. More than 50 % of CF patients are associated with Pseudomonas aeruginosa infection in their lungs which requires antibiotics such as Aztreonam (AZT). In this study, we prepared inhalable AZT-loaded lipid nanoparticles using Hot-melt extrusion (HME) coupled with probe sonication to target Pseudomonas aeruginosa infection in the lungs. The optimized nanoparticles were tested for physicochemical properties, stability profile, in-vitro aerosolization, and antimicrobial activity against Pseudomonas aeruginosa. The optimized nanoparticles with a PEI concentration of 0.1 % demonstrated a uniform particle size of <50 nm, a spherical shape observed under a transmission electron microscope, and >70 % drug entrapment. Incorporating cationic polymer, PEI, resulted in sustained drug release from the lipid nanoparticles. The in-vitro aerosolization studies exhibited a mass median aerodynamic diameter (MMAD) of <4.3 µm, suggesting deposition of the nanoparticles in the respirable airway. The antimicrobial activity against Pseudomonas aeruginosa showed the minimum inhibitory concentration of the formulation is 2-fold lower than plain AZT. Stability profile showed the formulations are stable after exposure to accelerated conditions. In conclusion, hot-melt extrusion in combination with probe sonication can be used as a potential method for the continuous production of AZT-loaded lipid nanoparticles with enhanced anti-bacterial activity.

Minocycline and Diacetyl Minocycline Eye Drops Reduce Ocular Neovascularization in Mice.

Purpose: To evaluate the efficacy of minocycline and a novel, modified minocycline analogue that lacks antimicrobial action, diacetyl minocycline (DAM), on choroidal neovascularization (CNV) in mice of both sexes. Methods: CNV was induced via laser injury in female and male C57BL/6J mice. Minocycline, DAM, or saline was administered via topical eye drops twice a day for 2 weeks starting the day after laser injury. CNV volume was measured using immunohistochemistry labeling and confocal microscopy. Results: Minocycline reduced lesion volume by 79% (P ≤ 0.0004) in female and male mice. DAM reduced lesion volume by 73% (P ≤ 0.001) in female and male mice. There was no significant difference in lesion volume between minocycline and DAM treatment groups or between female and male mice. Conclusions: Both minocycline and DAM eye drops significantly reduced laser-induced CNV lesion volume in female and male mice. While oral tetracyclines have been shown to mitigate pathologic neovascularization in both preclinical studies and clinical trials, the present data are the first to suggest that tetracycline derivatives may be effective to reduce pathologic CNV when administered via topical eye drops. However, the action is unrelated to antimicrobial action. Targeted delivery of these medications via eye drops may reduce the potential for systemic side effects. Translational Relevance: Topical administration of minocycline and/or DAM via eye drops may represent a novel therapeutic strategy for disorders involving pathologic CNV.

The preparation of lipid-based drug delivery system using melt extrusion.

Melt extrusion of lipids is versatile with high applicability in the pharmaceutical industry. The formulations prepared can be easily customized depending on the requirements, and have the potential to open a window on personalized medicine.