Conventional eye drops are associated with several limitations, including rapid drug clearance and low bioavailability, with only about 5% of the administered drug reaching the cornea to demonstrate therapeutic efficacy. Thus, to address these challenges, indomethacin (IND)-loaded microemulsion (Me)-embedded soft contact lenses (CLs) were developed to improve ocular drug delivery. The D-optimal mixture design was employed to optimize the composition of the Me formulation. Independent variables included Capmul MCM (oil phase), S mix (Tween 80/isopropyl alcohol), and water, while dependent variables were the globule size, transmittance (%), and drug release profile. The optimized Me exhibited a globule diameter of 45.69 ± 1.85 nm and a transmittance of 99.4% ± 1.59%. The globule dispersion index (PDI) was 0.33 ± 0.06, and the zeta potential (ZP) was 0.657 ± 0.012 mV. Soft CLs were developed using free radical polymerization and fortified with the Me loaded with the drug through direct loading and soaking techniques. Direct loading achieved a swelling percentage of 96.37% ± 1.8% and a transmittance of 96.5% ± 0.3%, while soaking resulted in 97.57% ± 1.4% swelling and 97.3% ± 1.3% transmittance. A drug content of 19.76 ± 0.23 μg per lenses for direct loading and 29.8 ± 0.2 μg per lenses for soaking demonstrated that the efficacy of the soaking technique was higher than that of direct loading. Moreover, drug release studies showed that the Me-laden lenses prepared using the direct loading technique released 44.00% ± 0.53% to 53.00% ± 0.59% of the drug within the first 6 h, while the lenses prepared via soaking released 62.58% ± 1.56% to 97.64% ± 1.52% of the drug within the first 6 h, followed by regulated drug release for up to 28 h, maintaining clarity and drug loading. Ocular irritancy test results indicated negligible irritation, suggesting that the Me-laden lenses are a safe and effective platform to manage ocular inflammation with the controlled delivery of IND.
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