title: A nanoparticle formulation reduces the corneal toxicity of indomethacin eye drops and enhances its corneal permeability.
abstract: Indomethacin (IMC) has been shown to reduce post-operative inflammation and to decrease intraocular irritation after cataract extraction and in cystoid macular edema; however, the clinical use of its most commonly used eye drops is limited due to topical side-effects that include burning sensation, irritation and epithelial keratitis. It is known that decreasing direct cell stimulation and reducing the amount applied via increasing bioavailability are useful for improving these issues. In this study, we designed ophthalmic formulations containing 0.5% IMC nanoparticles using zirconia beads and Bead Smash 12 (IMCnano eye drops; particle size 76 ± 59 nm, mean ± S.D.), and investigated the corneal toxicity of these IMCnano eye drops. IMCnano eye drops are tolerated better by a human cornea epithelial cell line (HCE-T) than commercially available NDSAIDs preparations (IMC, pranoprofen, diclofenac, bromfenac and nepafenac eye drops), and corneal wound healing in rat eyes with debrided corneal epithelium instilled with IMCnano eye drops is significantly better than that of eyes instilled with commercially available IMC eye drops. In addition, the accumulation of IMC in HCE-T cells treated with the IMCnano eye drops for 30 min was 19.9% that of the accumulation from commercially available IMC eye drops. On the other hand, the corneal penetration of IMC from IMCnano eye drops was significantly greater than in the case of the commercially available IMC eye drops in both in vivo and in vitro studies using rabbit corneas. Taken together, we hypothesize that a nanoparticle formulation reduces the corneal toxicity of IMC eye drops, probably because the accumulation of IMC from IMCnano eye drops in the eye is lower than that from commercially available IMC eye drops. In addition, the nanoparticle formulation may allow a decrease in the amount of IMC used due to the increase in bioavailability, resulting in reduced drug toxicity. These findings provide significant information that can be used to design further studies aimed at developing less toxic eye drops.
authors.affiliation: Faculty of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Nagai
authors.affiliation: Faculty of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan. Electronic address: itoyoshi@phar.kindai.ac.jp.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Ophthalmology, Kinki University, Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Okamoto
authors.affiliation: Department of Ophthalmology, Kinki University, Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Shimomura
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000737:chemistry; D058491:Bacterial Load; D001548:Benzalkonium Compounds / Q000008:administration & dosage / Q000737:chemistry; D002460:Cell Line; D003315:Cornea / Q000187:drug effects* / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D008353:Mannitol / Q000737:chemistry; D008747:Methylcellulose / Q000737:chemistry; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009883:Ophthalmic Solutions / Q000008:administration & dosage* / Q000737:chemistry; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D014945:Wound Healing / Q000187:drug effects; D015040:Zirconium / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001548:Benzalkonium Compounds; D009883:Ophthalmic Solutions; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D008353:Mannitol; D008747:Methylcellulose; D015040:Zirconium; C028541:zirconium oxide; D007213:Indomethacin
keywords: Corneal toxicity; Eye drops; Indomethacin; Nanoparticle; Transcorneal penetration