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.
Highlights
Glaucoma is an acquired disease that results in characteristic changes in the optic nerve head, and leads to vision impairment and blindness [1,2,3,4,5,6]
We have found that the co-instillation of magnesium hydroxide (MH, brucite) nanoparticles enhances the corneal penetration of dissolved timolol without observable corneal stimulation or obstruction of the nasolacrimal duct [23]
The mean particle size of carteolol/MH microparticle fixed combination was 7.2 μm, and the particle size was reduced to 73.5–113.5 nm by bead mill treatment (Figure 1A,C,E). nCMFC is stable for at least 8 days, since the particle size remained in the nano range for 8 days after preparation (Figure 1B,D)
Summary
Glaucoma is an acquired disease that results in characteristic changes in the optic nerve head, and leads to vision impairment and blindness [1,2,3,4,5,6]. Treatment with topical eye drops is considered a first choice of therapy for glaucoma, and medications such as β-blockers, prostaglandin analogs, adrenergic agonists, sympathomimetics, carbonic anhydrase inhibitors, α2 adrenergic agonists, and α1-blockers are all used clinically [1,2,3,4,5,6]. It has been reported that carteolol can ameliorate retrobulbar hemodynamics in patients with primary open-angle glaucoma [10,11,12], and improves ocular perfusion of the optic nerve head in healthy humans [10,13,14]. The remaining drug that enters the systemic circulation can cause bronchial asthma via antagonism of β-adrenoceptors. From these reasons, improvement of carteolol bioavailability is expected
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