Preparation of a new fixed-combination carteolol-netarsudil ophthalmic solution via one-pot pH-adjusting solubilization strategy for glaucoma treatment.

Abstract

Currently, the commercial fixed-combination of two agents is facing several clinical challenges, including suboptimal intraocular pressure (IOP) reduction, which requires multiple daily administrations, compromised bioavailability due to rapid tear film clearance and nasolacrimal drainage, and preservative-induced ocular surface toxicity. To address these limitations, we intend to develop a novel preservative-free, long-acting fixed-combination formulation of carteolol hydrochloride and netarsudil dimesylate. This once-daily formulation demonstrates enhanced therapeutic potential through optimized physicochemical stability and extended ocular residence time in theory. However, commercialized netarsudil dimesylate is precipitated when the pH of the solution is above 5.4 or when carteolol hydrochloride is mixed with netarsudil dimesylate. Consequently, the preservative-free and long-acting fixed-combination carteolol-netarsudil containing hydroxypropyl methylcellulose (HPMC) as a thickener (FC-CN-TKN) was prepared in a pH about 5.0 solution using an extremely simple one-pot pH-adjusting solubilization strategy, achieving stable co-solubilization of both active pharmaceutical ingredients. The optimized FC-CN-TKN formulation demonstrated excellent physicochemical stability under refrigerated storage conditions. Additionally, FC-CN exerted no influence on the intraocular penetration of each active compound in the pharmacokinetic study, and HPMC-mediated viscosity enhancement significantly prolonged precorneal retention, further improving its residence time and bioavailability. Importantly, once daily, FC-CN-TKN exerted a potent IOP-lowering effect and protective effect on retinal ganglion cells. The innovative FC-CN-TKN was stable, safe, and effective, being a promising glaucoma therapy.