International Journal of Nanomedicine (Aug 2021)

Fixed-Combination Eye Drops Based on Fluorometholone Nanoparticles and Bromfenac/Levofloxacin Solution Improve Drug Corneal Penetration

  • Otake H,
  • Goto R,
  • Ogata F,
  • Isaka T,
  • Kawasaki N,
  • Kobayakawa S,
  • Matsunaga T,
  • Nagai N

Journal volume & issue
Vol. Volume 16
pp. 5343 – 5356

Abstract

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Hiroko Otake,1,* Ryoka Goto,1,* Fumihiko Ogata,1 Takumi Isaka,1 Naohito Kawasaki,1 Shinichiro Kobayakawa,2 Toru Matsunaga,3 Noriaki Nagai1 1Faculty of Pharmacy, Kindai University, Higashi-Osaka, Osaka, 577-8502, Japan; 2Department of Ophthalmology, Nippon Medical School, Musashi-Kosugi Hospital, Kawasaki, Kanagawa, 211-8533, Japan; 3Design and Development, SEED Co., Ltd., Kounosu-shi, Saitama, 369-0131, Japan*These authors contributed equally to this workCorrespondence: Noriaki NagaiFaculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka, 577-8502, JapanTel +81 6 4307 3640Fax +81 6 6730 1394Email [email protected]: The multi-instillation of three commercially available (CA) eye drops [fluorometholone (FL)-, bromfenac (BF)- and levofloxacin (LV)-eye drops] has been used to manage pain and inflammation post-intraocular surgery. However, the multi-instillation of these three eye drops causes corneal damage, and the FL drops have the disadvantage of low ocular bioavailability. To overcome these problems, we prepared fixed-combination eye drops based on FL nanoparticles (FL-NPs) and BF/LV solution (nFBL-FC), and evaluated the corneal toxicity and transcorneal penetration of the nFBL-FC eye drops.Methods: FL powder was mixed in 2-hydroxypropyl-β-cyclodextrin solution containing benzalkonium chloride, mannitol and methylcellulose, and milled with a Bead Smash 12 (5500 rpm for 30 s× 30 times). The BF/LV solution was then added to the milled-dispersions to be used as nFBL-FC. The FL, BF and LV concentrations were measured by HPLC methods, and transcorneal penetration was evaluated in rabbits.Results: The FL particle size in nFBL-FC was 40– 150 nm, with only 0.0018% in liquid form. No aggregation of FL particles in the nFBL-FC was observed for 1 month. The viability of human corneal epithelial cells treated with nFBL-FC was remarkably higher than that of cells subjected to the multi-instillation of the corresponding three CA-eye drops. In addition, the corneal penetrations (AUC) of the FL, BF and LV in nFBL-FC were 4.9-, 1.8-, and 7.1-fold those of the corresponding CA-eye drops, respectively. Moreover, the caveolae-dependent endocytosis (CavME) inhibitor (nystatin) significantly prevented the transcorneal penetration of these drugs.Conclusion: We prepared fixed-combination eye drops based on FL-NPs and BF/LV solution (nFBL-FC), and show that high levels of FL-NPs and dissolved BF/LV (liquid drugs) can be delivered into the aqueous humor by the instillation of nFBL-FC. Further, we show that CavME is mainly related to the enhancement of transcorneal penetration of both the solid (NPs) and liquid drugs.Keywords: fluorometholone, bromfenac, levofloxacin, fixed-combination eye drops, corneal permeability, endocytosis

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