(122b) Effect of Hydrogel Formulation on Vitamin E Uptake and in Vitro Drug Release Kinetics for Improved Drug Release from Contact Lenses

Introduction. The most prevalent delivery method for common ophthalmic medications is eye drops ^1,2. However, eye drops have a low bioavailability of approximately 5% and a low average residence time in the eye of two minutes ^1,3,4. The rest of the drug is absorbed into the conjunctivitis and nose, allowing most of the drug to enter the blood stream and reach systemic circulation, raising concerns about side effects and toxicity ^1,5. Eye drops pose an additional problem for individuals who wear contact lenses as they must first remove their contact lenses, apply the eye drops, wait for the drug to be absorbed, and then reinsert their lenses. Ultimately, poor compliance to frequent dosing regimens and a low bioavailability make eye drops an inefficient solution for delivering ophthalmic drugs, and there is a need for improved drug delivery to the eye.

Thus, the use of contact lenses to deliver drugs has been explored. Contact lenses made from silicone or hydroxyethyl methacrylate (HEMA) hydrogel can be can be loaded with drugs either through dissolving the drug into the water phase of the lens ^6,7 or through binding the therapeutic to the polymer matrix ^8,9. Contact lenses do not require surgery or frequent application, and it is expected that they will improve patient compliance as it is estimated that 45 million people in the US wear contact lenses¹⁰. A remarkable advantage of drug release from contact lenses compared with eye drops is the drug released from the contact lens has a longer residence time in the post lens tear film (POLTF) than eye drop residence time in the tear film, leading to higher flux into the cornea ¹¹. Plus, contact lenses will reduce the drug inflow into the nasolacrimal sac, which will reduce uptake into the bloodstream ¹². Yet, drug release only occurs for a few short hours from commercial lenses loaded by drug soaking ^13–20. To address the issues of low drug loading and short release times, our group has extensively researched how the addition of vitamin E barriers to contact lenses can extend the release of drugs to days or weeks ^7,21,22.

The current study sought to determine the effect of lens composition on vitamin E uptake and drug release kinetics in order to improve the future use of contact lenses for extended drug delivery.

Methods. Molds for lenses were 3D printed. The silicone hydrogels were prepared by polymerizing a high ion permeability hydrophilic monomer along with a high oxygen permeability silicone monomer. Dimethylacrylamide (DMA) was used as the hydrophilic monomer, 3-methacryloxypropyltris(trimethylsiloxy)silane (TRIS) as the hydrophobic monomer and bis-alpha,omega-(methacryloxypropyl) polydimethylsiloxane as the macromer to ensure solubilization of these two components. Additionally, 1-vinyl-2 pyrrolidone (NVP) was added to increase water content and ethylene glycol dimethacrylate (EGDMA) was added for controlled crosslinking. Silicone hydrogels of several different compositions were prepared by free radical bulk polymerization of the monomers using UV photoinitiation with 2,4,6-trimethylbenzoyl-diphenyl-phosphineoxide (TPO). The various silicone formulations measured are shown in Table 1.

HEMA lenses were prepared by adding HEMA, water, and EGDMA in different ratios. Plus, vitamin-E barriers were added to the different formulations. This was done by soaking the lens in a vitamin-E ethanol solution for 24 hours, followed by soaking in water for 3 hours and then dipping quickly in ethanol to remove surface bound vitamin-E. The water content of the lenses was measured by weighing their dry weight and hydrated weights. Vitamin-E loading was also measured by weighing dry lenses before and after vitamin-E loading protocol. Cyclosporine, a model hydrophobic drug, was loaded into the lenses by soaking the lenses in a cyclosporine-PBS solution until equilibrium. Then the lenses were transported to PBS and the release of cyclosporine was measured over time using UV-Vis spectrometry.

Results. The vitamin E loaded and water uptake of the various lens formulations can be seen in Table 2. Form 2 has most DMA (hydrophilic monomer) and highest water content of silicone lens formulations. Form 1 has the most TRIS (hydrophobic monomer) and highest vitamin E loading of silicone lenses. Comparing Form 6 to 8, 8 has increased NVP. There was not a significant difference in vitamin E or water content (two tailed t-test alpha 0.05). Form 3 had the lowest DMA also lowest water content.

Release plots are shown in Figure 1. For release, forms 1-8 all were still releasing up to 50 days. Forms 2 and 4 which both had low amounts of TRIS released the most cumulative cyclosporine at 70 μg. By adding the vitamin-E barriers, release was significantly slowed down and only ~20 μg was released from the formulations in 40 days compared to ~50-70 μg without vitamin-E. HEMA lenses released all loaded cyclosporine (35 μg) in 12 days. However, release was extended from HEMA lenses when vitamin-E barriers were added, and were still releasing at 30 days. Release plots are being analyzed for partition and diffusivity coefficients.

Conclusion. By manipulating the formulations for the hydrogels, vitamin E uptake and cyclosporine release can be significantly changed. More cyclosporine loading can be achieved along with slower release profiles. Future work will focus on calculating diffusivity coefficients of cyclosporine from the lens to quantitatively evaluate the lens property effects on release. In addition, other lens properties such as oxygen and ion transport will also be evaluated. Moreover, a model hydrophilic drug (e.g. timolol) will also be analyzed for release.

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