PURPOSE: Drug therapy of tuberculosis (TB) requires long-term oral administration of multiple drugs for curing as well as preventing and/ or combating multi-drug resistance. Persistent, high blood levels of antitubercular drugs resulting from prolonged oral administration of anti-TB drugs may be neither necessary nor sufficient to kill mycobacteria residing in macrophages (M4). Inhalable biodegradable microparticles containing two of the first-line anti-TB drugs, isoniazid (H), and rifampicin (R), were prepared and tested for (i) phagocytosis by mouse Mphi. (ii) administration as a dry powder inhalation to rats, and (iii) targeting alveolar Mphi with high drug doses when administered to rats. METHODS: poly(D-L lactic acid) microparticles were prepared by emulsion methods and their drug content and size distribution determined. These were tested for uptake by murine Mphi in culture and resultant intracellular drug concentrations determined by high performance thin-layer chromatography (HPTLC). Rats were administered an inhalation of microparticles using an inhalation chamber developed in the lab. The extent of microparticle delivery in vivo was examined by flow-cytometry. Drug concentrations in the blood and in alveolar Mphi were estimated by high-performance liquid chromatography after oral, vascular. intratracheal, and inhalation administration. RESULTS: Inhalable microparticles could be prepared and were taken up by cultured Mphi. Large numbers of particles could be delivered to the bronchiopulmonary system through a 2-min exposure to fluidized particles. The intracellular drug concentrations resulting from vascular delivery of soluble drugs were found to be lower than those resulting from particle inhalation. CONCLUSIONS: Inhalable microparticles containing multiple anti-TB drugs offer promises of dose and dosing-frequency reduction, toxicity alleviation, and targeting Mphi-resident persistent mycobacteria.
PURPOSE: Drug therapy of tuberculosis (TB) requires long-term oral administration of multiple drugs for curing as well as preventing and/ or combating multi-drug resistance. Persistent, high blood levels of antitubercular drugs resulting from prolonged oral administration of anti-TB drugs may be neither necessary nor sufficient to kill mycobacteria residing in macrophages (M4). Inhalable biodegradable microparticles containing two of the first-line anti-TB drugs, isoniazid (H), and rifampicin (R), were prepared and tested for (i) phagocytosis by mouse Mphi. (ii) administration as a dry powder inhalation to rats, and (iii) targeting alveolar Mphi with high drug doses when administered to rats. METHODS:poly(D-L lactic acid) microparticles were prepared by emulsion methods and their drug content and size distribution determined. These were tested for uptake by murine Mphi in culture and resultant intracellular drug concentrations determined by high performance thin-layer chromatography (HPTLC). Rats were administered an inhalation of microparticles using an inhalation chamber developed in the lab. The extent of microparticle delivery in vivo was examined by flow-cytometry. Drug concentrations in the blood and in alveolar Mphi were estimated by high-performance liquid chromatography after oral, vascular. intratracheal, and inhalation administration. RESULTS: Inhalable microparticles could be prepared and were taken up by cultured Mphi. Large numbers of particles could be delivered to the bronchiopulmonary system through a 2-min exposure to fluidized particles. The intracellular drug concentrations resulting from vascular delivery of soluble drugs were found to be lower than those resulting from particle inhalation. CONCLUSIONS: Inhalable microparticles containing multiple anti-TB drugs offer promises of dose and dosing-frequency reduction, toxicity alleviation, and targeting Mphi-resident persistent mycobacteria.
Authors: Z Zwolska; H Niemirowska-Mikulska; E Augustynowicz-Kopec; R Walkiewicz; H Stambrowska; A Safianowska; H Grubek-Jaworska Journal: Int J Tuberc Lung Dis Date: 1998-10 Impact factor: 2.373
Authors: John Gar Yan Chan; Anneliese S Tyne; Angel Pang; Hak-Kim Chan; Paul M Young; Warwick J Britton; Colin C Duke; Daniela Traini Journal: Pharm Res Date: 2013-11-16 Impact factor: 4.200
Authors: Tammy W Shen; Catherine A Fromen; Marc P Kai; J Christopher Luft; Tojan B Rahhal; Gregory R Robbins; Joseph M DeSimone Journal: Pharm Res Date: 2015-05-23 Impact factor: 4.200