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Frances Lasowski, Moiz Mikail, Talena Rambarran, Heather Sheardown; Covalently-Incorporated Roscovitine Drug Delivery from Contact Lenses. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1190.
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© ARVO (1962-2015); The Authors (2016-present)
Contact lenses are viable as an alternative to eye drops as they can act as a slow release delivery vehicle, increase the residence time of the drugs and improve the bioavailability of these drugs in the ocular tissues. We have investigated this previously for roscovitine, a CDK inhibitor postulated to prevent retinoblastoma in children, where we demonstated sustained release with direct loading of roscovitine; however, the usefulness of this is limited by practical considerations regarding the extraction of silicone lenses. Therefore, the presence of a labile bond was explored to extend this release and limit it to aqueous conditions. Lactide spacers previously used in other drug delivery systems were explored in this work.
As seen in Figure 1, a lactide spacer was examined to covalently attach roscovitine to the model contact lenses previuosly developed in the Sheardown lab. Briefly, the lactide spacer was attached to the PEGMA monomer with the resulting terminal hydroxyl group opening the succinic anhydride ring. This produced a terminal carboxylic acid moiety, to which the alcohol moiety of the roscovitine was added using diisopropyl carbodiimide. NMR was used to confirm the conjugations. Optical transmittance and equilibrium water content were examined. Drug release was done into 1mL PBS with the solution changed at regular intervals.
NMR showed the conjugation of the drug to the PEGMA was sufficiently high for incorporation with the model lenses. Preliminary results, shown in Figure 2, show a slower, more sustained release profile with the presence of lactide spacers compared to the control sample which utilized direct incorportation of roscovitine (blue line). The length of the lactide spacer (2-10 lactide units) has a mild effect on the release rate of the drug. However, all tethered samples have a substantially reduced initial burst of drug and the release profile is close to the ideal zero-order kinetics over the first week. The water content and optical transparency of the modified samples remain within commerical standards.
An industrially-relevant contact lens drug delivery system can be obtained by covalently attaching roscovitine with a lactide spacer, overcoming previous problems experienced when loading during synthesis.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
Figure 1. Synthetic scheme for a lactide spacer crosslinked system.
Figure 2. Drug release from model contact lens materials.
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