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Research Article
Preparation of Polymeric Micelles for use as Carriers of Tuberculostatic Drugs
Márcia Silva1*, Eiizabeth I. Ferreira2, Clarice Q. F. Leite3, and Daisy N. Sato4,
1epartamento de Fármacos e Medicamentos, Faculdade de Ciências Farmacêuticas, Unesp, Araraquara – SP, Brazil
2epartamento de Farmácia, Faculdade de Ciências Farmacêuticas, USP, São Paulo – SP, Brazil
3epartamento de Ciências Biológicas, Faculdade de Ciências Farmacêuticas, Unesp, Araraquara – SP, Brazil
4nstituto Adolfo Lutz, Ribeirão Preto – SP, Brazil
Tropical Journal of Pharmaceutical Research December 2007; 6(4): 815-824
ISSN: 1596-599
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 anti-mycobacterial 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.
Keywords: pyrazinamide, isoniazid, rifampin, tuberculostatic prodrugs, polymer micelles
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*Corresponding Author: Tel.: 055-16-33016971, Fax: 055-16-33016960; email: silvam@fcfar.unesp.br