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Diffusion-Based Design of Multi-Layered Ophthalmic Lenses for Controlled Drug Release.

ABSTRACT: The study of ocular drug delivery systems has been one of the most covered topics in drug delivery research. One potential drug carrier solution is the use of materials that are already commercially available in ophthalmic lenses for the correction of refractive errors. In this study, we present a diffusion-based mathematical model in which the parameters can be adjusted based on experimental results obtained under controlled conditions. The model allows for the design of multi-layered therapeutic ophthalmic lenses for controlled drug delivery. We show that the proper combination of materials with adequate drug diffusion coefficients, thicknesses and interfacial transport characteristics allows for the control of the delivery of drugs from multi-layered ophthalmic lenses, such that drug bursts can be minimized, and the release time can be maximized. As far as we know, this combination of a mathematical modelling approach with experimental validation of non-constant activity source lamellar structures, made of layers of different materials, accounting for the interface resistance to the drug diffusion, is a novel approach to the design of drug loaded multi-layered contact lenses.

SUBMITTER: Pimenta AF

PROVIDER: S-EPMC5147977 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo evaluate the recent practice of design and statistical analysis of ophthalmic randomized clinical trials (RCTs).DesignReview of 96 ophthalmic RCTs.MethodsTwo authors (R.D., G.S.Y.) reviewed primary result papers published from January 2020 through December 2021 in Ophthalmology, JAMA Ophthalmology, American Journal of Ophthalmology, and British Journal of Ophthalmology. Data were extracted and analyzed for the characteristics of design (1-eye design, 2-eye design, paired-eye design, and subject design), sample size and power, and statistical analysis for intereye correlation adjustment, missing data, and correction for multiplicity.Main outcome measuresCharacteristics of trial design and statistical analysis.ResultsAmong 96 RCTs, 50 (52%) used 1-eye design, 21 (22%) 2-eye design, 10 (10%) paired-eye design, and 15 (16%) subject design. In 31 trials of 2-eye design or paired-eye design, 18 (58%) trials had suboptimal analysis of data from both eyes by analyzing data from 1 eye (n = 10), taking the average of 2 eyes (n = 2), analyzing 2 eyes separately (n = 1), ignoring intereye correlation (n = 3), or not specifying how 2-eye data were analyzed (n = 2), and 13 trials (42%) properly adjusted the intereye correlation by using the mixed-effects model (n = 6), paired t test (n = 5), generalized estimating equations (n = 1), or marginal Cox regression model (n = 1). Among 96 trials, 75 (78%) provided both sample size and statistical power estimation, and 16 (17%) trials described statistical test for sample size or power estimation. Missing data in primary outcome occurred in 86 (90%) trials with a median missing data rate of 8%, 32 (37%) trials applied statistical methods for missing data, including last value carried forward (n = 10), multiple imputation (n = 14), or other approaches (n = 8). Among 25 trials with > 2 arms, 16 (64%) corrected for multiplicity using the Bonferroni procedure (n = 8), Hochberg procedure (n = 2), Gatekeeping procedure (n = 2), or hierarchical procedure (n = 4). Among 16 trials with multiple primary outcomes, 4 (25%) corrected for multiplicity by the Bonferroni procedure.ConclusionsThere are opportunities for improvement in the design and statistical analyses of ophthalmic trials, particularly in the aspects of adjustment for intereye correlation, missing data, and multiplicity. Continuing education in ophthalmology and vision research community may improve the quality of ophthalmic trials.Financial disclosuresProprietary or commercial disclosure may be found after the references.

Project description:Design of advanced contact lenses (CLs) demands materials that are safe and comfortable for the wearers and that preserve the normal eye microbiota, avoiding chronic inflammation and biofilm development. This work aimed to combine the natural antibiofouling phosphorylcholine and the antioxidant and prebiotic resveratrol as integral components of CLs that may have the additional performance of preventing oxidative-stress related eye diseases. Different from previous uses of 2-methacryloyloxyethyl phosphorylcholine (MPC) as coating, we explored the feasibility of adding MPC at high proportions as a comonomer of 2-hydroxyethyl methacrylate (HEMA)-based hydrogels while still allowing for the loading of the hydrophobic resveratrol. Homogeneous distribution of MPC along the hydrogel depth (confirmed by Raman spectroscopy) notably increased solvent uptake and the proportion of free water while it decreased Young's modulus. Relevantly, MPC did not hinder the uptake of resveratrol by CLs (>10 mg/g), which indeed showed network/water partition coefficients of >100. Protocols for CLs sterilization and loading of resveratrol under aseptic conditions were implemented, and the effects of tear proteins on resveratrol release rate were investigated. CLs sustained resveratrol release for more than 24 h in vitro, and sorption of albumin onto the hydrogel, although attenuated by MPC, slowed down the release. The combination of MPC and resveratrol reduced P. aeruginosa and S. aureus growth as tested in a novel hydrogel disk-agar interface biofilm growth setup. The developed CLs showed excellent anti-inflammatory properties and biocompatibility in in ovo and rabbit tests and provided higher and more prolonged levels of resveratrol in tear fluid, which favored resveratrol biodistribution in anterior and posterior eye segments compared to eye drops. Correlations between the release profiles of resveratrol in vitro and in vivo were assessed. Relevantly, the CLs preserved the antioxidant properties of resveratrol during the entire 8 h of wearing. In sum, CLs prepared with high proportion in MPC may help address safety and comfort requirements while having drug releasing capabilities.

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Diffusion-Based Design of Multi-Layered Ophthalmic Lenses for Controlled Drug Release.

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