Synthesis and characterization of polymeric derivatives of isoniazid as anti-tuberculosis drugs
Conventional method for treatment of tuberculosis requires efficient therapy systems due to inefficiency of drug administration and multi drug resistance. In recent years of many studies were carried out to improve drug delivery systems. Polymers are one of the most essential elements for drug deliv...
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| Format: | Thesis |
| Language: | English English |
| Published: |
2014
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| Subjects: | |
| Online Access: | https://eprints.ums.edu.my/id/eprint/38931/1/24%20PAGES.pdf https://eprints.ums.edu.my/id/eprint/38931/2/FULLTEXT.pdf |
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| Summary: | Conventional method for treatment of tuberculosis requires efficient therapy systems due to inefficiency of drug administration and multi drug resistance. In recent years of many studies were carried out to improve drug delivery systems. Polymers are one of the most essential elements for drug delivery research due to their versatility. By the approach of multivalency, drug delivery studies gained new vision. Polymers with multiple site of attachment were used to create multivalent interactions. In this research, natural polymer, chitosan was used as polymeric drug carrier. Chitosan was initially modified to enhance it as an efficient drug carrier. Chitosan was etherified with monochloro acetic acid to produce carboxymethyl chitosan. N-acylation was carried out onto carboxymethyl chitosan to produce Nsuccinylcarboxymethyl chitosan. N-succinylcarboxymethyl chitosan was then coupled with a known anti-tuberculosis drug, isoniazid to produce multivalent isoniazid. A series of 12 compounds were successfully synthesized. The evaluations of chemical and physical properties of multivalent isoniazid compounds were conducted after purification by dialysis. Several factors affecting the synthesis of multivalent isoniazid such as temperature and reaction medium were studied. Among the 12 compounds compound C had highest degree of substitution value with 0.36 and it is considered as the most efficient drug substituted compound. The optimum reaction condition for producing compound C with DS value 0.36 was 50 0C with water and isopropanol at 2:8 reaction medium. Isoniazid and Nsuccinylcarboxymethyl chitosan interactions and changes in properties were determined by FTIR analysis. From FTIR spectroscopy analysis, the existence of isoniazid transmittance bands in synthesised multivalent compounds with slight changes indicated that isoniazid chemically interacted with NSCMCS. The SEM micrograph observation also reconfirmed the substitution process, the unmodified chitosan had smooth surface whereas rough features observed on the multivalent compounds. Particle size measurement revealed the synthesized compound has larger radius size than isoniazid. Compound C has the largest radius with 954.1 nm whereas the radius of isoniazid was 110.8 nm. Large size of compound has the ability to prolong the circulating duration. Drug stability profile of synthesized compounds was studied in pH buffer 3.5 and 7.4. Results revealed that the release of isoniazid was more stable in alkaline medium. This also indicated that isoniazid cleaved from N-succinylcarboxymethyl chitosan backbone through hydrolysis as it linked through amide. The solubility profile showed that the final compounds not soluble towards the water, however carboxymethyl chitosan and Nsuccinylcarboxymethyl chitosan does soluble in water. Finallyantimycobacterial assay was done against M. tuberculosis H37Rv. The results revealed that compound A was the most potent drug as it inhibits the M. tuberculosis with isoniazid concentration of 1.5822 mg/mL. The minimum inhibitory concentration value obtained was 0.0781 μg/mL.By this study, the efficiency of the multiplicity effect in drug delivery was shown. |
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