Synthesis, Characterisation And In Vitro Evaluation Of Disulphide Cross-Linked Polymers As Potential Carriers For Colon Specific Drug Delivery System
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Date
2015-02
Authors
Lau, Yong Khee
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Publisher
Universiti Sains Malaysia
Abstract
Colon drug delivery system is very useful to deliver drugs for treatment of localised colonic diseases such as inflammatory bowel disease, ulcerative colitis and Crohn’s disease. Disulphide cross-linked polymer has received much attention because of its ability to act as a redox sensitive polymer and will only be cleaved by the low redox potential environment in the colon. Recently, branch-chained disulphide polymers had received more attention due to the fact that it is less susceptible for degradation in low pH condition of the stomach compared to linear-chained disulphide polymers. Therefore, the aim of this work is to synthesise tricarballylic acid based trithiol monomer for polymerisation into branch-chained disulphide polymers. The synthesised polymers were characterised, studied chemically and evaluated using in vitro disintegration studies. The monomer was synthesised by amide coupling reaction between tricarballylic acid and (triphenylmethyl) thioethylamine by using two synthetic steps. The monomer was deprotected using trifluoroacetic acid and triethylsilane to expose the sulphur atoms in preparation for further polymerisation. White powdery solid was obtained with yield around 20-25%. Spectroscopic and CHNS elemental analysis results complemented with the desired monomer. FT-IR showed the presence of amide peaks and supported by the mass analysis using LC-MS. The oxidative polymerisation of N,N',N''-tris(2-sulfanylethyl)propane-1,2,3-tricarboxamide (trithiol monomer) and 2,2’-(ethylenedioxy)diethanethiol (dithiol monomer) of various molar ratios resulted six (6) different polymers, namely, P10, P11, P12, P15, P21 and P51. Raman spectroscopy demonstrated the emergence of disulphide bond. Chemical reduction studies showed that all the disulphide polymers were completely reduced after 1 hour of reduction with different thiol concentrations. In simulated gastric and intestinal condition, all the polymers showed low thiol concentrations when compared to the detected thiol concentrations in simulated colon condition with the presence of Bacteroides fragilis. The results proved that all the disulphide polymers were able to withstand the harsh environment of the gastric and intestinal condition and degradation will only occur in the colon condition with the presence of anaerobic colonic bacteria. Disintegration was found to be more pronounced in polymer P15 as the highest thiol concentration of 57 x 10-6 mol L-1 among all the other polymers. This result correlated the general consensus that biodegradability relies on the swelling ability of polymers in an aqueous environment. This work has successfully identified a disulphide cross-linked polymer, which might be potential for colon specific targeting. However, further study on these polymers is required to establish the stability and use of the polymer within a pharmaceutical dosage form.
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Keywords
Disulphide polymers