Analytical Method for Transdermal Delivery of the Anti-angiogenic Compound TNP-470

Pathological angiogenesis is a critical component in cancer, in chronic systemic inflammatory diseases such as psoriasis and rheumatoid arthritis, and in ocular diseases. Anti-angiogenic drugs have the ability to prevent, inhibit, and regress newly formed blood vessels. The activity of TNP-470 (chloro acetylcarbamoylfumagillol), a potent anti-angiogenic drug, has been demonstrated in numerous preclinical studies and in eight clinical studies involving more than three hundred patients. Despite its encouraging efficacy, TNP-470 is unstable compound with short plasma half-life, and, as was found clinically it can cause neurotoxicity side-effects at high doses. In light of these limitations, developing a transdermal drug delivery for TNP-470, can offer a novel and promising clinical usage for this drug by improving its bioavailability, controlled dosage and safety profile. In this work, we developed a reliable method for skin permeation studies of TNP-470, using the pig skin in Franz diffusion cells and High-Performance Liquid Chromatography (HPLC) analysis. Additionally, we performed a broad stability and degradation studies of TNP-470 in different mediums and identify optimal stabilizing conditions in acetate buffer pH-4.5, which can be used for transdermal formulation. Our results demonstrated excellent permeability properties of TNP-470 through the pig skin, where 25% from the initial amount was crossed through the skin membrane after 72 hours. Our results suggesting that TNP-470 is a good candidate for transdermal drug delivery, whereas, an optimal dermal formulation would improve drug’s pharmacokinetic properties and toxicity profile by introducing it in a slow release system.