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Background: We prepared magnesium hydroxide nanoparticles (MH-NPs) by a bead mill method, andinvestigated whether the co-instillation of MH-NPs improves the low transcorneal penetration of water-solubledrugs, such as the anti-glaucoma eye drug timolol maleate (TM). Materials and Methods: The TM was solved insaline containing additives (0.5% methylcellulose, 0.001% benzalkonium chloride, 0.5% mannitol; TM-solution).MH-NPs were prepared by a bead mill method with additives. Then MH microparticle/TM and MH-NPs/TM fixedcombinations (mMTFC and nMTFC) were prepared by mixing the TM-solution and MH particles. Thetranscorneal penetration and intraocular pressure (IOP)-reducing effect of TM was evaluated in rabbits. Results:MH particle size was decreased by the bead mill treatment to a mean particle size of 71 nm. In addition, the MH-NPs were highly stable. Next, we demonstrated the effect of MH-NPs on the corneal surface. MH shows onlyslight solubility in lacrimal fluid, and the instillation of MH-NPs for 14 days did not affect the behavior (balance ofsecretion and excretion) of the lacrimal fluid in rabbit corneas. Moreover, there was no observable cornealtoxicity of MH-NPs, and treatment with MH-NPs enhanced the intercellular space ratio in the eyes of rats. MHalone did not permeate into the cornea; however, the co-instillation of MH-NPs and dissolved TM (nMTFC)enhanced the corneal penetration of TM. In addition, the IOP-reducing effect of nMTFC was significantly higherthan those of the TM solution or the co-instillation of MH microparticles and TM. Conclusion: We found that MH-NPs enhance the corneal penetration of dissolved TM with no observable corneal stimulation or obstruction ofthe nasolacrimal duct by the MH-NPs. It is possible that the co-instillation of MH-NPs may provide a useful wayto improve the bioavailability of water-soluble drugs in the ophthalmic field. These findings provide significantinformation that can be used to design further studies aimed at developing anti-glaucoma eye drugs.