In situ gelation of thiolated poly(aspartic acid) derivatives through oxidant-free disulfide formation for ophthalmic drug delivery

Szilágyi, Barnabás Áron and Gyarmati, Benjámin Sándor and Kiss, L. Eszter and Budai-Szűcs, Mária and Misra, Anil and Csányi, Erzsébet and László, Krisztina and Szilágyi, András (2023) In situ gelation of thiolated poly(aspartic acid) derivatives through oxidant-free disulfide formation for ophthalmic drug delivery. COLLOIDS AND SURFACES B: BIOINTERFACES. ISSN 0927-7765

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Abstract

Efficient topical treatment of ocular diseases requires a prolonged residence time of drug formulations. An in situ gelling, mucoadhesive system can provide improved residence time while keeps the installation of the formulation easy and accurate due to its low initial viscosity. We synthesized a two-component, biocompatible water-based liquid formulation showing in situ gelation. S protected, preactivated derivatives of thiolated poly(aspartic acid) (PASP-SS-MNA) were synthesized by coupling of the free thiol groups of thiolated poly(aspartic acid) (PASP-SH) with 6-mercaptonicotinic acid (MNA). The amount of protecting groups was found to be 242, 341 and 530 µmol/g depending on the degree of thiolation of PASP. The interaction between PASP-SS-MNA and mucin was proven indicating the mucoadhesive properties. Disulfide cross-linked hydrogels were formed in situ without an oxidizing agent by mixing the aqueous solutions of PASP-SS-MNA and PASP-SH. The gelation time was controlled between 1 and 6 min, while the storage modulus was as high as 4 to 16 kPa depending on the composition. Swelling experiments showed that hydrogels with no residual thiol groups are stable in phosphate-buffered saline at pH = 7.4 whereas the presence of free thiol groups leads to the dissolution of the hydrogel with a rate depending on the excess of thiol groups. Biological safety of the polymers and 6-mercaptonicotinic acid was confirmed on Madin-Darby Canine Kidney cell line. Furthermore, a prolonged release, compared to a conventional liquid formulation, of ofloxacin was observed at pH = 7.4, supporting the potential of the developed biopolymers in ophthalmic drug delivery.

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