title: Rifapentine-loaded PLGA microparticles for tuberculosis inhaled therapy: Preparation and in vitro aerosol characterization.
abstract: Inhaled delivery of drugs incorporated into poly (lactic-co-glycolic acid) (PLGA) microparticles allows a sustained lung concentration and encourages phagocytosis by alveolar macrophages that harboring Mycobacterium tuberculosis. However, limited data are available on the effects of physicochemical properties of PLGA, including the monomer ratio (lactide:glycide) and molecular weight (MW) on the aerosol performance, macrophage uptake, and toxicity profile. The present study aims to address this knowledge gap, using PLGAs with monomer ratios of 50:50, 75:25 and 85:15, MW ranged 24 - 240kDa and an anti-tuberculosis (TB) drug, rifapentine. The PLGA-rifapentine powders were produced through a solution spray drying technique. The particles were spherical with a smooth surface and a volume median diameter around 2μm (span ~2). When the powders were dispersed using an Osmohaler(®) at 100L/min for 2.4s, the fine particle fraction (FPFtotal, wt.% particles in aerosol <5μm relative to the total recovered drug mass) was ranged between 52 and 57%, with no significant difference between the formulations. This result suggests that the monomer ratio and MW are not crucial parameters for the aerosol performance of PLGA. The phagocytosis analysis was performed using Thp-1 monocyte-derived macrophages. The highest rate of uptake was observed in PLGA 85:15 followed by 75:25 and 50:50 with about 90%, 80% and 70%, respectively phagocytosis over 4h of exposure. Furthermore, the cytotoxicity analysis on Thp-1 and human lung adenocarcinoma epithelial cells demonstrated that PLGA concentration up to 1.5mg/mL, regardless of the monomer composition and MW, were non-toxic. In conclusion, the monomer ratio and MW are not crucial in determining the aerosol performance and cytotoxicity profile of PLGA however, the particles with high lactide composition have a superior tendency for macrophage uptake.
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, 2006 NSW, Australia.
authors.forename: Thaigarajan
authors.initials: T
authors.lastname: Parumasivam
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, 2006 NSW, Australia.
authors.forename: Sharon S Y
authors.initials: SS
authors.lastname: Leung
authors.affiliation: Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney, 2006 NSW, Australia.
authors.forename: Diana Huynh
authors.initials: DH
authors.lastname: Quan
authors.affiliation: Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney, 2006 NSW, Australia.
authors.forename: Jamie A
authors.initials: JA
authors.lastname: Triccas
authors.affiliation: Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney, 2006 NSW, Australia; Tuberculosis Research Program, Centenary Institute, Newtown 2042 NSW, Australia.
authors.forename: Warwick J
authors.initials: WJ
authors.lastname: Britton
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, 2006 NSW, Australia. Electronic address: kim.chan@sydney.edu.au.
authors.forename: Hak-Kim
authors.initials: HK
authors.lastname: Chan
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols / Q000737:chemistry; D000995:Antitubercular Agents / Q000737:chemistry*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D008168:Lung / Q000166:cytology; D008855:Microscopy, Electron, Scanning; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012293:Rifampin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000336:Aerosols; D000995:Antitubercular Agents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D012293:Rifampin; C018421:rifapentine
keywords: Aerosols; Molecular weight; Monomer ratio; Poly (lactic-co-glycolic acid); Rifapentine