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A. Prinz, M. Hornof, A. Clausen, M. Hoffer; Design of Ocular Inserts Based on Thiolated Anionic and Cationic Polymers. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5772. doi: https://doi.org/.
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To develop mucoadhesive and cohesive ocular inserts based on thiolated chitosan and thiolated hyaluronic acid for controlled drug delivery to the tear fluid.
Chitosan and hyaluronic acid were modified with thiol groups via covalent attachment of N-acetylcysteine and cysteamine, respectively. Ocular inserts (diameter: 2 mm, weight: 1.6 mg) were prepared by direct compression of polymer mixtures at different weight ratios. The dissolution behavior of inserts in artificial tear fluid was evaluated in vitro as well as the release kinetics of the model substances diclofenac (MM 318 Da) and horseradish peroxidase (MM 40 kDa).
Thiolated chitosan and hyaluronic acid contained 190 µM and 75 µM thiol groups per gram polymer, respectively. Dissolution behavior of the inserts was influenced considerably by the matrix composition. When modifying the weight ratio of the two polymeric excipients the in vitro dissolution time of the inserts varied from a few minutes to more than one week. In addition to the formation of a polyion complex between chitosan and hyaluronic acid the insert matrix was stabilised by the formation of intermolecular disulfide bonds. Release of diclofenac was influenced by the insert composition as well. From the most stable insert formulations diclofenac was released within 15h to18h following almost zero-order kinetics. In the case of fast dissolving inserts release of the drug correlated with the dissolution time of the formulation, but still occured at a controlled rate within 2h to 10h. Due to its high molecular weight the protein peroxidase was released at a much slower rate. Insert formulations, which were stable for more than one week, released the enzyme in 1 to 7 days depending on the ratio of thiolated hyaluronic acid and thiolated chitosan in the insert matrix.
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