Nano delivery of antitubercular drugs to the brain: pharmacokinetic and therapeutic implications in mice model of tuberculous meningitis

Abstract

Abstract Tuberculous meningitis is the most severe form of extrapulmonary tuberculosis. Though it represents approximately 1% of all cases of tuberculosis, it causes mortality or severe disabilities in almost fifty percent of the patients affected. Current treatment of the disease involves the use of Isoniazid, Rifampicin, and Pyrazinamide which is associated with a number of drawbacks like the limited ability of antitubercular drugs to cross the blood-brain barrier, hepato and nephrotoxicity issues, lengthy treatment schedule, and patient non-compliance. To overcome the limitations, Polybutylcyanoacrylate (PBCA) nanoparticles encapsulating anti-tubercular drugs were synthesized by anionic polymerization and double coated with PEG+P-80 for oral delivery of drugs to the brain. Nanoparticles were in nanosize range and sterically stable. Pharmacokinetic analysis showed sustained release of drugs in the plasma for about 96h and their retention in the brain for up to 12 days after single dose oral administration of nanoencapsulated antitubercular drugs. A murine model of tuberculous meningitis was developed by intracranial administration of Mycobacterium tuberculosis H37Rv in mice and chemotherapeutic efficacy of nano-encapsulated drugs was evaluated in the infected mice model. Drug-loaded PBCA nanoparticles were found to be more effective than free drugs for the treatment of tuberculous meningitis as 4 or 8 doses of the nano-encapsulated formulation were equi-efficacious to 32 or 64 doses of free drugs administered daily.