Thiolated and S-protected hydrophobically modified cross-linked poly(acrylic acid) – A new generation of multifunctional polymers

• Cysteine was covalently attached to the backbone of alkylated polyacrylate (AC1030).
• Free thiol groups of thiolated AC1030 were S-protected by 2-mercaptonicotinic acid.
• Thiolated and S-protected AC1030 exhibits emulsifying properties.
• Mucoadhesion of thiolated and S-protected AC1030 was 4- and 18-fold improved.
• Thiolated and S-protected AC1030 showed sustained release for a lipophilic drug.

The aim of this study was to create a novel multifunctional polymer by covalent attachment of l-cysteine to the polymeric backbone of hydrophobically modified cross-linked poly(acrylic acid) (AC1030). Secondly, the free thiol groups of the resulting thiomer were activated using 2-mercaptonicotinic acid (2-MNA) to provide full reactivity and stability. Within this study, 1167.36 μmol cysteine and 865.72 μmol 2-MNA could be coupled per gram polymer. Studies evaluating mucoadhesive properties revealed a 4-fold extended adherence time to native small intestinal mucosa for the thiomer (AC1030-cysteine) as well as an 18-fold prolonged adhesion for the preactivated thiomer (AC1030-Cyst-2-MNA) compared to the unmodified polymer. Modification of the polymer led to a higher tablet stability concerning the thiomer and the S-protected thiomer, but a decelerated water uptake could be observed only for the preactivated thiomer. Neither the novel conjugates nor the unmodified polymer showed severe toxicity on Caco-2 cells. Evaluation of emulsification capacity proofed the ability to incorporate lipophilic compounds like medium chain triglycerides and the preservation of the emulsifying properties after the modifications. According to these results thiolated AC1030 as well as the S-protected thiolated polymer might provide a promising tool for solid and semisolid formulations in pharmaceutical development.

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