Co-Administration of MPC Polymer Enhances the Ocular Absorption and Intraocular Pressure-Lowering Effect of Timolol Maleate

Hiroko Otake,1 Fumihiko Ogata,1 Naohito Kawasaki,1 Ayano Sasaki,2 Ryuya Gotanda,2 Yosuke Matsuoka,2 Noriaki Nagai1 1Faculty of Pharmacy, Kindai University, Higashi-Osaka, Osaka, 577-8502, Japan; 2Life Science Division, NOF CORPORATION, Shibuya-ku, Tokyo, 150-6012, JapanCorrespondence: Noriaki Nagai, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka, 577-8502, Japan, Tel +81 6 4307 3638, Fax +81 6 6730 1394, Email nagai_n@phar.kindai.ac.jpPurpose: We previously developed a novel 2-methacryloyloxyethyl phosphorylcholine-based polymer (MPCP) containing a zwitterionic stearyl methacrylate moiety and an acrylic functional group, which significantly improved moisture retention on the ocular surface. In this study, we investigated whether incorporating 0.1% MPCP into 0.25% or 0.5% timolol maleate (TM) ophthalmic formulations could enhance the ocular surface retention, corneal permeability, and intraocular pressure (IOP)-lowering efficacy of TM.Methods: Male Wistar rats (7 weeks old) and male adult rabbits (body weight: 2.39 ± 0.71 kg) were used to evaluate ocular surface retention and corneal permeability of TM. IOP-lowering efficacy of TM was evaluated using a rabbit treated with 5% glucose solution (high IOP model).Results: The TM ophthalmic formulations with MPCP (TM@MPCP-OF) were transparent, with MPCP nanoparticles (mean particle size 80.7 nm) dispersed in the formulation, and exhibited stable viscosity, regardless of the presence of MPCP (approximately 0.95– 1.1 mPa∙s). The addition of MPCP reduced cytotoxicity in human corneal epithelial cells (HCE-T) and caused no damage after repeated instillation in rats. Moreover, the combination with MPCP improved TM retention on the ocular surface and increased the corneal TM concentration and aqueous humor penetration after the instillation of TM@MPCP-OF. In addition, the corneal permeability-enhancing effect of MPCP on the TM was more pronounced with TM@MPCP-OF containing 0.5% TM than with TM@MPCP-OF containing 0.25% TM. Furthermore, compared with the TM ophthalmic formulation alone, MPCP co-administration significantly prolonged the duration and magnitude of the IOP-lowering effect of TM in a rabbit model of acute ocular hypertension.Conclusion: These findings indicate that MPCP is a safe and biocompatible additive that enhances the pharmacological performance of ophthalmic formulations and may contribute to the development of improved and longer-acting antiglaucoma medications. On the left, Timolol is shown with arrows indicating high ocular surface retention, middle corneal permeability and low intraocular-lowering effect. On the right, combination of Timolole and MPCP is depicted with arrows showing middle ocular surface retention, low corneal permeability and high intraocular-lowering effect. The legend at the top explains the arrow types: solid for high, dashed for middle, dotted for low and dash-dotted for minimum. The illustration highlights differences in drug effects on eye physiology.Diagram: Timolol vs. MPCP on eye surface retention, corneal permeability and eye pressure.