title: Inhalable microparticles containing drug combinations to target alveolar macrophages for treatment of pulmonary tuberculosis.
abstract: OBJECTIVE
  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.affiliation: Pharmaceutics Division, Central Drug Research Institute, Lucknow, India.
authors.forename: R
authors.initials: R
authors.lastname: Sharma
authors.forename: D
authors.initials: D
authors.lastname: Saxena
authors.forename: A K
authors.initials: AK
authors.lastname: Dwivedi
authors.forename: A
authors.initials: A
authors.lastname: Misra
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D016503:Drug Delivery Systems; D005434:Flow Cytometry; D006863:Hydrogen-Ion Concentration; D007538:Isoniazid / Q000008:administration & dosage / Q000627:therapeutic use; D016676:Macrophages, Alveolar / Q000187:drug effects*; D051379:Mice; D008863:Microspheres; D010316:Particle Size; D010587:Phagocytosis / Q000187:drug effects; D051381:Rats; D012293:Rifampin / Q000008:administration & dosage / Q000627:therapeutic use; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000995:Antitubercular Agents; D007538:Isoniazid; D012293:Rifampin