Preparation of Polymeric Micelles for use as Carriers of Tuberculostatic Drugs

Abstract

Purpose: This paper focuses on the characterization of polymeric micelle-forming tuberculostatic prodrugs and the antimycobacterial activity of these prodrugs. Method: By the condensation of hydroxymethylpyrazinamide, isoniazid and rifampin with free carboxyl groups on the copolymer poly(ethyleneglycol)-poly(aspartic acid), micelle-forming carrier-drug conjugates were obtained. These micelles were characterized by dynamic light scattering, to measure the micelle diameter; by acid-base titration, to determine the percentage of carboxylic groups occupied by the tuberculostatic; by Sudan III solubility tests, to estimate the critical micelle concentration (CMC); and visual control and spectrophotometric measurement, to determine the stability of micelles. These micelles were tested in vitro against several Mycobacterium strains. Results: As expected, the size and distribution of the micelle-forming tuberculostatic prodrugs found to be small (78.2nm, 84.2nm and 98.9 nm) while the level of the drug conjugated was high (65.02-85.7%). Furthermore, the micelles were stable in vitro, exhibiting a low level of CMC and stronger antimycobacterial activity than the original drugs. Conclusion: The results demonstrate that polymeric micelles can be used as efficient carriers for drugs, which alone, exhibit undesired pharmacokinetics, poor solubility, and low stability. The synthesized micelle-forming tuberculostatic prodrugs opens a perspective of alternative prodrugs that prolong action and decrease the toxicity of the tuberculostatic drugs of choice.

Present status of nanoparticle research for treatment of Tuberculosis

“…A 5.6-fold increase in anti-tuberculosis activity against M. tuberculosis was found for micelle-forming prodrug as compared to the free drug [86]. Similar attempts were made to incorporate PYZ and RIF in micelles ( <100 nm) aiming to minimize renal filtration and prolonging mean residence times in the blood stream with improved antimicrobial activity [87,88]. INH lipid derivatives was designed by Jin et al to reduce the resistance.…”

Nanotechnology: A focus on Treatment of Tuberculosis.

“…The mechanism would primarily involve the micelle uptake and the latter intracellular release of the drug after the hydrolysis of the linkage. The same synthetic pathway was pursued in order to encapsulate PYZ [46,47] and RIF [47]. The size of themicelles would prevent renal filtration, increasing the residence times in the blood stream.…”

Tackling the Problem of Tuberculosis by Nanotechnology

“…It was expected that when the drugs are released after internalization of micelle, by cleavage, they act as pro-drugs and enhance solubility of hydrophobic drugs, reduce drug toxicity, increase bioavailability, specificity, and systematic release of drugs, and prolong the drug action (Moghimi et al, 1993;Croy and Kwon, 2006;Dadwal, 2014). Micelle-forming polymer derivatives of the initial-phase Anti-TB drugspyrazinamide, thioridazine, isoniazid, and rifampin-showed potential activity against drug-resistant bacteria (Silva et al, 2007;Amaral and Viveiros, 2012). This potentiates the drug activity when conjugated to the polymer and, hence, is promising with regard to the possible reductions in the dose.…”