Développement d’une lentille cornéenne médicamentée
The development of corneal contact lenses initially aimed to correct vision troubles but more recently targets to improve administration of ophthalmic drugs. Eye drops from ophthalmic solutions has a poor administration efficiency of 5% or less and is currently the most used method to deliver drugs to the eye. Such administration technique needs to be improved and contact lenses could be the solution according to many opticians. However, no marketed therapeutic contact lenses has been marketed up to date. In this project we have developed a model of a contact lens made of 2-(hydroxyethyl)methacrylate embedding microgels of poly N-isopropylacrylamide (pNIPAM), encapsulating a model drug. We first developed an analytical method capable to quantify simultaneously seven ophthalmic drugs: Pilocarpine, lidocaine, proparacaine, atropine, triamcinolone acetonide, timolol and prednisolone. This method was developed on a HPLC-MS/MS device and was validated according to FDA and ICH criteria. Using this method, we achieved very low detection and quantitation limits with high precision and accuracy in both simulated lachrymal fluids and in rabbit ocular tissues. Each seven drugs was validated using this method. We proceeded with the synthesis of negatively charged microgels of NIPAM using methacrylic acid (MAA) as comonomer. Resulting size were ranging between 200-600 nm and zeta potential was found to increase (absolute value) with temperature. The microgels were used to encapsulate a model molecule, rhodamine 6G (R6G), in different medium and were loaded in the microgel up to 38% (drug loading, DL%). Using Langmuir isotherms to measure affinity and adsorption of R6G, it was found well correlated to MAA content in microgels, suggesting electrostatic interaction was the main parameter for drug loading. Release kinetics was performed using a model hydrogel of acrylamide embedding the R6G-loaded microgels. The measured release was found to follow an affinity-based mechanism for over 4-24 hours. The release kinetics were then compared to a formulation of liposomes and nanogels of chitosan embedded in hydrogel. All formulations exhibited interesting release profiles making them promising systems for different therapeutic applications. Finally, we changed the acrylamide gels for pHEMA designed to reproduce contact lenses containing drug-loaded microgels. The hydrogel composition, in terms of monomer / cross-linker ratio, was first optimized to fit contact lenses properties of 260-340 µm thick contact lenses. We also made use of semi-interpenetrated polyvinylpirrolidone (PVP) in the pHEMA hydrogel matrix to increase its water content. The highest DL% of negatively charged microgels were obtained using lidocaine and were used for release studies, where the total content of lidocaine was released in approximately 2 hours with and without microgels. In the end, this was a pilot study aiming to evaluate the potential of microgel usability in contact lenses. However, the impact of microgels on release was not fully conclusive. Additional studies should be undertaken to achieve a better comprehension and characterization of the release mechanism such as using more eye relevant physiological models. Such studies would provide further insights on the use of such materials for eye drug delivery and its applicability.
Microgels HPLC-MS/MS Nanostructures Hydrogel Corneal contact lenses Controlled release