Tyrosine kinase inhibitors (TKIs) can inhibit edema and neovascularization, such as in age-related macular degeneration and diabetic retinopathy. However, their topical administration in ophthalmology is limited by their toxicity and poor aqueous solubility. There are multiple types of TKIs, and each TKI has an affinity to more than one type of receptor. Studies have shown that ocular toxicity can be addressed by selecting TKIs that have a high affinity for specific vascular endothelial growth factor receptors (VEGFRs) but a low affinity for epidermal growth factor receptors (EGFRs). Drugs permeate from the aqueous tear fluid into the eye via passive diffusion. Thus, a sustained high concentration of the dissolved drug in the aqueous tear fluid is essential for a successful delivery to posterior tissues such as the retina. Unfortunately, the aqueous solubility of the TKIs that have the most favorable VEGFR/EGFR affinity ratio, that is, axitinib and cabozantinib, is well below 1 µg/mL, making their topical delivery very challenging. This is a review of the drug-like properties of TKIs that are currently being evaluated or have been evaluated as ophthalmic drugs. These properties include their solubilization, cyclodextrin complexation, and ability to permeate from the aqueous tear fluid to the posterior eye segment.
Most of the TKIs in development are administered by ocular injection or as implants, but few are being developed for topical application. The use of topically effective TKIs in the form of aqueous eye drops can offer a more patient-friendly approach to treating retinal conditions.
Although dovitinib is not a good candidate for the treatment of posterior eye conditions, such as AMD, it serves as a good example of how the formulation of an aqueous drug/CD eye drop microsuspension can deliver lipophilic and poorly soluble drugs to the posterior eye segment. The experimental solubility of dovitinib in pure water was determined to be between 0.2 and 0.5 µg/mL and increases to approximately 650 µg/mL in a pure aqueous 5 % (w/v) γCD solution at pH 6.5 and ambient temperature.
Phatsawee Jansook, Thorsteinn Loftsson, Einar Stefánsson (2024) Drug-like properties of tyrosine kinase inhibitors in ophthalmology: Formulation and topical availability. International Journal of Pharmaceutics 655, 124018. https://doi.org/10.1016/j.ijpharm.2024.124018.