Chemotherapeutic efficacy of nanoparticle encapsulated antitubercular drugs.
Our objective was to evaluate the chemotherapeutic potential of oral poly lactide-co-glycolide (PLG, a synthetic polymer) nanoparticle encapsulated ethambutol in combination with PLG-nanoparticle encapsulated-(rifampicin + isoniazid + pyrazinamide) in a murine tuberculosis (TB) model. Our formulation was prepared by the multiple emulsion technique and administered orally to mice for the biodistribution, pharmacokinetic, and chemotherapeutic studies. A single oral administration of the formulation to mice could maintain sustained drug levels in the plasma for 5 days and in the organs (lungs, liver, spleen) for 7-9 days. There was a striking improvement in the pharmacokinetic parameters such as half-life and mean residence time as compared with free drugs. The relative/absolute bioavailability of the 4 antituberculosis drugs was enhanced several fold. Repeated administration of the formulation did not produce any hepatotoxicity as assessed on a biochemical basis. In M. tuberculosis H37Rv infected mice, just 3 oral doses of the 4-drug formulation administered at every 10th day resulted in undetectable bacilli in the organs replacing 28 conventional doses of free drugs. We concluded that polymeric nanoparticle based oral 4-drug combination bears significant potential to shorten the duration of TB chemotherapy, besides reducing the dosing frequency.
Pandey
Rajesh
R
Department of Biochemistry, Postgraduate Institute of Medical Education & Research, Chandigarh, India.
Sharma
Sadhna
S
Khuller
G K
GK
D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D001682:Biological Availability; D004359:Drug Therapy, Combination; D004977:Ethambutol / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006207:Half-Life; D007538:Isoniazid / Q000493:pharmacokinetics / Q000627:therapeutic use; D019344:Lactic Acid; D008297:Male; D051379:Mice; D049329:Nanostructures; D010316:Particle Size; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D011718:Pyrazinamide / Q000493:pharmacokinetics / Q000627:therapeutic use; D012293:Rifampin / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
D000995:Antitubercular Agents; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D011718:Pyrazinamide; D019344:Lactic Acid; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin