Daylight-Mediated, Passive, and Sustained Release of the Glaucoma Drug Timolol from a Contact Lens

Abstract

Timolol, a potent inhibitor of β-adrenergic receptors (βARs), is a first-line drug for decreasing the intraocular pressure (IOP) of patients with glaucoma. Timolol is administered using 0.5% eye-drop solutions at >3 × 107 times the inhibitory concentration (ki) for βARs. This high dose is wasteful and triggers off-target effects that increase medication noncompliance. Here, we introduce contact lenses that release timolol to the eye throughout the day during passive exposures to natural daylight at a more therapeutically relevant concentration (>3000 ki). Timolol is coupled to the polymer of the contact lens via a photocleavable caged cross-linker and is released exclusively to the surrounding fluid after the 400–430 nm mediated cleavage of the cross-linking group. Studies conducted in a preclinical mouse model of glaucoma show photoreleased timolol is effective as authentic timolol in reducing IOP. Our studies highlight several advantages of daylight-mediated release of timolol from lenses compared to eye-drops. First, fitted contact lenses exposed to natural daylight release sufficient timolol to sustain the inhibition of βARs over a 10 h period. Second, the contact lenses inhibit βARs in the eye using only 5.7% of the timolol within a single eye-drop. Third, the lenses allow the patient to passively control the amount of timolol released from the lens—for example, early morning exposure to outdoor sunlight would release enough timolol to maximally reduce the IOP, whereas subsequent periodic exposures to indoor daylight would release sufficient timolol to overcome the effects of its spontaneous dissociation from βARs. Fourth, our lenses are disposable, designed for single day use, and manufactured at a low cost.

An Engineered Contact Lens for Passive and Sustained Release of Lifitegrast, an Anti-Dry Eye Syndrome Drug

“…Polymerization of this solution at 80 °C for 1 hour resulted in the formation of transparent hydrogels having the form and stiffness of a daily-use contact lens for humans. 30 The functions of each component of the mixture are summarized as follows: HEMA was used as the backbone of the polymer; specific concentrations of DMAA and MMA were used to modulate the stiffness of the polymer; 4-Arm-PEG was used to increase the hydrophilicity of the polymer and helps to maintain water content. We employed AIBN as a heat-activated initiator.…”

“…Since the absorption of the photoprotection group crosslinker in the lens only extends to 430 nm, we would not expect it to impact color-perception, i.e., lenses are transparent over the visible range and indistinguishable in form and function to 2hydroxyethyl methacrylate (HEMA)-based disposable contact lenses. 30 Reaction Scheme 3. Co-polymerization of caged lifitegrast into contact lens hydrogel and subsequent release of authentic lifitegrast upon exposure to indoor daylight (400 -430 nm).…”

Therapeutic Ophthalmic Lenses: A Review

“…A different strategy was used to obtain daylight-mediated timolol release. The drug molecule was linked to the CL by a photocleavable caged cross-linker (dimethoxy-substituted 2-nitrobenzene caged group) [ 136 ]. Bond breakage was triggered by 400–430 nm light, and therapeutic amounts of timolol were released for 10 h. The estimated relative low fabrication cost would also allow for a daily lens disposal and it would avoid risks of contamination during reloading procedures.…”

Development and validation of analytical method by HPLC-DAD for determination of vasodilator active in pharmaceutical ophthalmic forms

“…Its therapy requires multiple daily instillations to obtain a suitable therapeutic response, but this may compromise patient's compliance. In addition, more than 90% of the administered dose is drained by the nasolacrimal duct, reaching the systemic circulation, which leads to adverse effects (Karki et al, 2016;Mu et al, 2018;Sharif, 2017;Zhu et al, 2018).…”

“…To overcome these problems many formulations have been developed, such as contact lenses (Carvalho et al, 2015;Desai et al, 2018, Alvarez-Lorenzo et al, 2019, nanosuspensions, nanoparticles (Gupta et al, 2010;Mu et al, 2018), polymeric nanocarriers (cyclodextrins, dendrimers) (Calles et al, 2015;Carta et al, 2015;Rodriguez-Aller et al, 2015), and lipid nanoparticles (Gooch et al, 2012;Wang et al, 2015Wang et al, , 2017. Ophthalmic inserts are another formulation that can be used.…”