Enhancement in Corneal Permeability of Dissolved Carteolol by Its Combination with Magnesium Hydroxide Nanoparticles

Abstract

We prepared magnesium hydroxide (MH) nanoparticles, and investigated their effect when combined with dissolved carteolol on the bioavailability and intraocular pressure (IOP)-reducing effect of carteolol. The carteolol was solved in saline containing additives (0.5% methylcellulose, 0.001% benzalkonium chloride, 0.5% mannitol; CRT-solution). MH nanoparticles were prepared by a bead mill method with additives. Then carteolol/MH microparticle and carteolol/MH nanoparticle fixed combinations (mCMFC and nCMFC) were prepared by mixing the CRT-solution and MH particles. The transcorneal penetration and IOP-reducing effect of carteolol was evaluated in rabbits. The mean particle size of mCMFC was 7.2 μm, and the particle size was reduced to 73.5–113.5 nm by the bead mill treatment. The MH particles in nCMFC remained in the nano size range for 8 days after preparation, and the amounts of lacrimal fluid and corneal damage were unchanged by repetitive instillation of nCMFC (twice a day for 4 weeks). The transcorneal penetration of carteolol was enhanced by the combination with MH nanoparticles, and the IOP-reducing effect of nCMFC was significantly higher than that of CRT-solution or mCMFC. In conclusion, we designed nCMFC, and showed that the high levels of dissolved carteolol can be delivered into the aqueous humor by the instillation of nCMFC. Combination with MH nanoparticles may achieve an enhancement of corneal penetration for water-soluble drugs. These findings provide significant information that can be used to design further studies aimed at developing anti-glaucoma eye drugs.

Dose- and Time-Dependent Cytotoxicity of Carteolol in Corneal Endothelial Cells and the Underlying Mechanisms

“…Carteolol is a major anti-glaucoma therapeutic drug, and it has been reported that prolonged and repeated use of anti-glaucoma medications probably provoke side-effects on HCECs, including low cell survival capacity, which imparts deep concern with regard the clinical safety of this therapeutic agent (Igarashi et al, 1990;Ayaki et al, 2008Ayaki et al, , 2009Nagai et al, 2018;Fuwa et al, 2019). Thus, research on the cytotoxic effects and the involved toxicological mechanisms of carteolol on corneal endothelial cells, both in vivo and in vitro, have crucial importance in providing reference points for the secure administration of carteolol in the eye clinic.…”

Therapeutic Potential of a Combination of Magnesium Hydroxide Nanoparticles and Sericin for Epithelial Corneal Wound Healing

“…The 1% sericin solution and nanoparticles (MHN) were prepared using a bead mill method reported by previous study [21,22,23,24]. The sericin ophthalmic formulations (Sericin/MH fixed combination) containing MHP (P-Ser) or MHN (N-Ser) were prepared by mixing the sericin solution and MH formulations (MHP and MHN).…”

“…The size of the MH particles N-Ser was determined by both a laser diffraction particle size analyzer SALD-7100 (Shimadzu Corp., Kyoto, Japan) and dynamic light scattering NANOSIGHT LM10 (Quantum Design Japan, Tokyo, Japan). The Atomic Force Microscope (AFM) images of MHNand N-Ser were provided by an SPM-9700 (Shimadzu Corp., Kyoto, Japan) [21,22].…”

“…The P-Ser and N-Ser formulations were preserved in the dark for 1 month at 20 °C, and the stability were evaluated [21,22]. The MH solubility in saline and lacrimal fluid of rabbits were determined using a Magnesium B test kit according to the manufacturer’s instructions.…”

“…Recently, we reported that the co-instillation of magnesium hydroxide (MH) nanoparticles (MHN) increases the ratio of the intercellular space in corneal epithelium (the intercellular area/ the intercellular plus epithelium area), resulting in an increase in intracellular uptake and corneal penetration of dissolved drugs such as timolol maleate and carteolol [21,22]. Thus, the co-instillation of MHN may be useful for enhancing the therapeutic effects of ophthalmic formulations by prolonging the time drugs remain on the cornea.…”