Analysis of release kinetics of ocular therapeutics from drug releasing contact lenses: Best methods and practices to advance the field.

Several methods have been proposed to achieve an extended and controlled release of ocular therapeutics via contact lenses; however, the experimental conditions used to study the drug release vary greatly and significantly influence the release kinetics. In this paper, we examine variations in the release conditions and their effect on the release of both hydrophilic and hydrophobic drugs (ketotifen fumarate, diclofenac sodium, timolol maleate and dexamethasone) from conventional hydrogel and silicone hydrogel lenses. Drug release was studied under different conditions, varying volume, mixing rates, and temperature. Volume had the biggest effect on the release profile, which ironically is the least consistent variable throughout the literature. When a small volume (2-30 mL) was used with no forced mixing and solvent exchange every 24 h, equilibrium was reached promptly much earlier than solvent exchange, significantly damping the drug release rate and artificially extending the release duration, leading to false conclusions. Using a large volume (200-400 mL) with a 30 rpm mixing rate and no solvent exchange, the release rate and total mass released was significantly increased. In general, the release performed in small volumes with no force mixing exhibited cumulative mass release amounts of 3-12 times less than the cumulative release amounts in large volumes with mixing. Increases in mixing rate and temperature resulted in relatively small increases of 1.4 and 1.2 times, respectively in fractional mass released. These results strongly demonstrate the necessity of proper and thorough analysis of release data to assure that equilibrium is not affecting release kinetics. This is paramount for comparison of various controlled drug release methods of therapeutic contact lenses, validation of the potential of lenses as an efficient and effective means of drug delivery, as well as increasing the likelihood of only the most promising methods reaching in vivo studies.

Adjusting biomaterial composition to achieve controlled multiple-day release of dexamethasone from an extended-wear silicone hydrogel contact lens.

PURPOSE: To alter the composition and structure of silicone hydrogel contact lenses to achieve controlled release of dexamethasone and evaluate the lens optical and mechanical properties compared to commercial lenses. There is a tremendous need for controlled release of drugs from ocular biomaterials as the majority of ophthalmic drugs are delivered via topical eye drops, which have low bioavailability and patient compliance. METHODS: Poly(PDMS-co-TRIS-co-DMA) contact lenses were synthesized with varying PDMS/TRIS:DMA ratios (0.25:1, 0.67:1, 1.5:1) as well as with additional crosslinking monomers. Lenses were characterized via in vitro release studies in a microfluidic device at ocular flowrates and in large well-mixed volumes, optical quality studies over visible wavelengths, mechanical analysis, and determination of polymer volume fraction in the swollen state. RESULTS: Extended and controlled release of therapeutically relevant concentrations of dexamethasone was achieved for multiple day, continuous wear up to 60 days at in vitro ocular flowrates. Release was delayed due to a combination of increased hydrophobic to hydrophilic composition and the inclusion of additional structural constraints, both of which decreased the polymer volume fraction in the swollen state. However, decreased mass release rates were at the expense of increased modulus and decreased lens flexibility. All lenses had high optical clarity (∼90% transmittance) and contained highly oxygen permeable siloxane composition similar to those found in commercial silicone hydrogel lenses, but they had poor flexibility for use as soft contact lenses. CONCLUSIONS: Based on our results, the lenses described herein likely have too high of a modulus for use as extended-wear, soft contact lenses with drug release. Therefore, other controlled release methods would be better suited for maintaining adequate mechanical properties and achieving controlled and extended release for the duration of wear in soft, silicone hydrogel contact lens biomaterials. However, these biomaterials may find clinical use as more rigid gas permeable contact lenses or inserts.

In vitro controlled release of an anti-inflammatory from daily disposable therapeutic contact lenses under physiological ocular tear flow.

Novel molecularly imprinted, therapeutic contact lenses capable of controlled release of the non-steroidal anti-inflammatory (NSAID) diclofenac sodium were synthesized, exploiting ionic non-covalent interactions. Poly(HEMA-co-DEAEM-co-PEG200DMA) soft contact lenses were prepared (105±5 µm thickness, diameter 15.0±0.2mm, base curve of 8.6±0.2mm) with different monomer to template ratios and dynamic release studies were conducted in artificial lacrimal solution using two different in vitro methods. Under infinite sink conditions, imprinted contact lenses demonstrated concentration dependent release kinetics. Under physiological flow rates, by increasing the M/T ratio from 1 to 10.5, the release rate decreased from 11.72 µg/h to 6.75 µg/h during the first 48 h. The release rate was more constant, moving toward zero-order release. To use these lenses as daily disposable lenses, the first 24h of release was studied and found to be linear with a rate of 17.27, 11.99, and 8.74 µg/h for M/T ratios of 1, 3.5, and 10.5, respectively. Furthermore, the lenses prepared with a M/T ratio of 10.5 released diclofenac at a rate close to the maximum dose delivered by commercial eye drops, making them ideal for use as daily disposable lenses, and potentially leading to better patient benefit with substantially increased efficacy.

Extended release of high molecular weight hydroxypropyl methylcellulose from molecularly imprinted, extended wear silicone hydrogel contact lenses.

Symptoms of contact lenses induced dry eye (CLIDE) are typically treated through application of macromolecular re-wetting agents via eye drops. Therapeutic soft contact lenses can be formulated to alleviate CLIDE symptoms by slowly releasing comfort agent from the lens. In this paper, we present an extended wear silicone hydrogel contact lens with extended, controllable release of 120 kDa hydroxypropyl methylcellulose (HPMC) using a molecular imprinting strategy. A commercial silicone hydrogel lens was tailored to release approximately 1000 µg of HPMC over a period of up to 60 days in a constant manner at a rate of 16 µg/day under physiological flowrates, releasing over the entire range of continuous wear. Release rates could be significantly varied by the imprinting effect and functional monomer to template ratio (M/T) with M/T values 0, 0.2, 2.8, 3.4 corresponding to HPMC release durations of 10, 13, 23, and 53 days, respectively. Lenses had high optical quality and adequate mechanical properties for contact lens use. This work highlights the potential of imprinting in the design and engineering of silicone hydrogel lenses to release macromolecules for the duration of wear, which may lead to decreased CLIDE symptoms and more comfortable contact lenses.