(56a) Feasibility of Corneal Drug Delivery of Cysteamine Using Vitamin E Modified Silicone-Hydrogel Contact Lenses

Cystinosis is an inherited genetic disease characterized by the accumulation of cystine crystals in several tissues including the cornea, which can cause irreversible damage.  The corneal manifestations of cystinosis are treated by hourly instillation of cysteamine eye drops each day for 6 to 8 times while awake.  The high frequency of eye drop instillation along with the long duration of treatment leads to poor compliance in many patients. In addition, cysteamine drug solutions are unstable and must include stabilizers and are stored at 4^oC to prevent oxidation of the free thiol group.  This is very inconvenient for cystinosis patients if the drug should keep at low temperature all the time. Contact lenses have shown to increase bioavailability due to increased residence time of the drug in the tear film sandwiched between the lens and the cornea. Thus, we have combined in vitroexperiments with mathematical modeling to investigate the feasibility of daily use of cysteamine loaded contact lenses to replace the hourly instillation of drops. We also examine the possibility that contact lenses may have the additional benefit of reducing the oxidation rate of cysteamine.     

Our approach was based on incorporation of vitamin E diffusion barriers into commercially available contact lenses to increase the duration of drug release.  Contact lenses were first soaked in a solution of vitamin E in ethanol.  Subsequently the lenses were soaked in an aqueous solution of cysteamine to load the drug.  The drug release profiles from vitamin E treated lenses were measured under sink conditions.  In addition, drug oxidation rates were measured after exposing drug loaded contact lenses to humidified room air.  To study further the feasibility of using contact lenses for the delivery of cysteamine, a mass transfer model was used to determine the rates at which the drug loaded in the lens is delivered to the cornea. 

The results show that vitamin E loading increases the release duration from 10 min to about 3 hours in solution, thus allowing the possibility of extended drug delivery.  The mathematical modeling of drug transport in the eye suggested that the vitamin E loaded contact lens can provide the daily therapeutic dose without causing toxicity, while significantly increasing the bioavailability compared to eye drops.  In addition to improving the release profiles and therapeutic efficiency, the oxidation rates of a hydrophilic drug cyteamine are significantly reduced by incorporation in biphasic silicone-hydrogel contact lenses likely because the drug partitions in the hydrophilic regions in contact lens which have a limited accessibility to oxygen, which primarily diffuses through the silicone phase.  We also showed that the oxidation rates can be further reduced with the incorporation of vitamin E diffusion barriers in the lens.

Cysteamine delivery by vitamin E modified contact lens is a very promising therapy for cystinosis patients due to its feasibility of solving potential problems of eye drops related to compliance and drug stability.  Based on the in vitro experimental results and the mathematical modeling, it is likely that a single contact lens worn for about 2 hours could achieve the same therapeutic effects as hourly instillation of eye drops.  The package of the contact lens can be easily designed to exclude oxygen and so the cysteamine loaded contact lens does not have to be stored in refrigerator. During the wearing period, the drug degradation in the contact lens can also be minimized by loading the drug in vitamin E modified silicone-hydrogel contact lenses.