Poly (DL-lactide-co-glycolide) nanoparticle-based inhalable sustained drug delivery system for experimental tuberculosis.
OBJECTIVE
To improve the bioavailability of antitubercular drugs (ATDs) as well as to assess the feasibility of administering ATDs via the respiratory route, this study reports the formulation of three frontline ATDs, i.e. rifampicin, isoniazid and pyrazinamide encapsulated in poly (DL-lactide-co-glycolide) nanoparticles suitable for nebulization.


METHODS
Drug-loaded nanoparticles were prepared by the multiple emulsion technique, vacuum-dried and nebulized to guinea pigs. The formulation was evaluated with respect to the pharmacokinetics of each drug and its chemotherapeutic potential in Mycobacterium tuberculosis infected guinea pigs.


RESULTS
The aerosolized particles exhibited a mass median aerodynamic diameter of 1.88 +/- 0.11 microm, favourable for bronchoalveolar lung delivery. A single nebulization to guinea pigs resulted in sustained therapeutic drug levels in the plasma for 6-8 days and in the lungs for up to 11 days. The elimination half-life and mean residence time of the drugs were significantly prolonged compared to when the parent drugs were administered orally, resulting in an enhanced relative bioavailability (compared to oral administration) for encapsulated drugs (12.7-, 32.8- and 14.7-fold for rifampicin, isoniazid and pyrazinamide, respectively). The absolute bioavailability [compared to intravenous (i.v.) administration] was also increased by 6.5-, 19.1- and 13.4-fold for rifampicin, isoniazid and pyrazinamide, respectively. On nebulization of nanoparticles containing drugs to M. tuberculosis infected guinea pigs at every 10th day, no tubercle bacilli could be detected in the lung after five doses of treatment whereas 46 daily doses of orally administered drug were required to obtain an equivalent therapeutic benefit.


CONCLUSIONS
Nebulization of nanoparticles-based ATDs forms a sound basis for improving drug bioavailability and reducing the dosing frequency for better management of pulmonary tuberculosis.
Pandey
Rajesh
R
Department of Biochemistry, Postgraduate Institute of Medical Education & Research, Chandigarh-160 012, India.
Sharma
Anjali
A
Zahoor
A
A
Sharma
Sadhna
S
Khuller
G K
GK
Prasad
B
B
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000627:therapeutic use* / Q000633:toxicity; D019540:Area Under Curve; D001682:Biological Availability; D055598:Chemical Phenomena; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D002627:Chemistry, Physical; D015169:Colony Count, Microbial; D004337:Drug Carriers; D004338:Drug Combinations; D004339:Drug Compounding; D005260:Female; D006168:Guinea Pigs; D006207:Half-Life; D007275:Injections, Intravenous; D007538:Isoniazid / Q000008:administration & dosage / Q000627:therapeutic use; D019344:Lactic Acid; D008168:Lung / Q000378:metabolism / Q000382:microbiology; D008297:Male; D008863:Microspheres; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010316:Particle Size; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D011718:Pyrazinamide / Q000008:administration & dosage / Q000627:therapeutic use; D012293:Rifampin / Q000008:administration & dosage / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
D000336:Aerosols; D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D004337:Drug Carriers; D004338:Drug Combinations; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D011718:Pyrazinamide; D019344:Lactic Acid; D007538:Isoniazid; D012293:Rifampin