Abstract
PurposePermeation studies, with near infrared (NIR) light and anti-aggregation antibody formulation, were used to investigate the in vitro permeation of bevacizumab, ranibizumab and aflibercept through human sclera.MethodsA vertical, spherical Franz cell diffusion apparatus was used for this scleral tissue permeation model. A photokinetic ocular drug delivery (PODD) testing device accommodated the placement of NIR LEDs above the donor chambers. An adjustable LED driver/square wave generator provided electrical energy with a variable pulse rate and pulse width modulation (duty cycle).ResultsExposure to non-thermal NIR light had no effect on mAbs with regard to monomer concentration or antibody binding potential, as determined by SE-HPLC and ELISA. The optimal LED wavelength was found to be 950 nm. Duty cycle power of 5% vs 20% showed no difference in permeation. When compared to controls, the combination of non-aggregating antibody formulation and NIR illumination provided an average transscleral drug flux enhancement factor of 3X.ConclusionNarrow wavelength incoherent (non-laser) light from an NIR LED source is not harmful to mAbs and can be used to enhance drug permeation through scleral tissue. The topical formulation, combined with pulsed NIR light irradiation, significantly improved scleral permeation of three anti-VEGF antibody drugs.
Highlights
The number of people visually impaired in the world is estimated to be 285 million, 39 million blind and 246 million having low vision; 65% of people visually impaired and 82% of all blind are 50 years and older. [1] Age-related macular degeneration (AMD) is a progressive, degenerative disease of the retina that occurs with increasing incidence with age and ranks third among the global causes of visual impairment. [1] Exudative AMD is caused by new, abnormal blood vessel growth in the subretinal layers, leading to vascular leaks, bleeding, and progressive vision loss. [2] Vascular endothelial growth factor (VEGF) is a signaling protein produced by macrophages, retinal pigment epithelium and Muller cells that stimulate vasculogenesis and angiogenesis
The bevacizumab concentrations obtained for the control and light exposed (NIR light) groups, as analyzed by Size-Exclusion High Performance Liquid Chromatography (SE-HPLC), were both about 550 ng/ml at 1 and 5 h, respectively
The bevacizumab concentrations obtained for the one hour control and light exposed group were about 550 ng/ml, using Enzyme-Linked Immunosorbent Assay (ELISA) as the analytical method
Summary
The number of people visually impaired in the world is estimated to be 285 million, 39 million blind and 246 million having low vision; 65% of people visually impaired and 82% of all blind are 50 years and older. [1] Age-related macular degeneration (AMD) is a progressive, degenerative disease of the retina that occurs with increasing incidence with age and ranks third among the global causes of visual impairment. [1] Exudative AMD is caused by new, abnormal blood vessel growth (neovascularization) in the subretinal layers, leading to vascular leaks, bleeding, and progressive vision loss. [2] Vascular endothelial growth factor (VEGF) is a signaling protein produced by macrophages, retinal pigment epithelium and Muller cells that stimulate vasculogenesis and angiogenesis. [3] Drugs such as the monoclonal antibodies, bevacizumab, ranibizumab and the fusion protein, aflibercept can inhibit VEGF and control or slow those diseases. [8] The majority of approved antibody drugs are used to treat cancer and inflammation Two of these monoclonal antibodies, bevacizumab (Avastin®) and FDA approved ranibizumab (Lucentis®), show antiVEGF properties and may be used to treat age related macular degeneration (AMD) and diabetic retinopathy. Anti-VEGF drugs are delivered by repeated intravitreal injections [15], which can bring about serious complications including retinal detachment and infection, as well as being painful and costly. Godley et al recently described their early work with photokinetics and the development of a device to deliver light energy, especially in the application of transscleral drug delivery, to the posterior segment of the eye. Godley et al recently described their early work with photokinetics and the development of a device to deliver light energy, especially in the application of transscleral drug delivery, to the posterior segment of the eye. [19] This strategy was applied and investigated as a simplified model of scleralvitreous interface and unstirred gel mimicking the vitreous. [21]
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