Fixed-Combination Eye Drops Based on Fluorometholone Nanoparticles and Bromfenac/Levofloxacin Solution Improve Drug Corneal Penetration
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-Kosu...
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Dove Medical Press
2021
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oai:doaj.org-article:037b0009a2d84b57b72ec4ccb7b4c5cd2021-12-02T16:39:26ZFixed-Combination Eye Drops Based on Fluorometholone Nanoparticles and Bromfenac/Levofloxacin Solution Improve Drug Corneal Penetration1178-2013https://doaj.org/article/037b0009a2d84b57b72ec4ccb7b4c5cd2021-08-01T00:00:00Zhttps://www.dovepress.com/fixed-combination-eye-drops-based-on-fluorometholone-nanoparticles-and-peer-reviewed-fulltext-article-IJNhttps://doaj.org/toc/1178-2013Hiroko 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 nagai_n@phar.kindai.ac.jpPurpose: 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, endocytosisOtake HGoto ROgata FIsaka TKawasaki NKobayakawa SMatsunaga TNagai NDove Medical Pressarticlefluorometholonebromfenaclevofloxacinfixed-combination eye dropscorneal permeabilityendocytosisMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 16, Pp 5343-5356 (2021) |
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DOAJ |
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fluorometholone bromfenac levofloxacin fixed-combination eye drops corneal permeability endocytosis Medicine (General) R5-920 |
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fluorometholone bromfenac levofloxacin fixed-combination eye drops corneal permeability endocytosis Medicine (General) R5-920 Otake H Goto R Ogata F Isaka T Kawasaki N Kobayakawa S Matsunaga T Nagai N Fixed-Combination Eye Drops Based on Fluorometholone Nanoparticles and Bromfenac/Levofloxacin Solution Improve Drug Corneal Penetration |
| description |
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 nagai_n@phar.kindai.ac.jpPurpose: 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 |
| format |
article |
| author |
Otake H Goto R Ogata F Isaka T Kawasaki N Kobayakawa S Matsunaga T Nagai N |
| author_facet |
Otake H Goto R Ogata F Isaka T Kawasaki N Kobayakawa S Matsunaga T Nagai N |
| author_sort |
Otake H |
| title |
Fixed-Combination Eye Drops Based on Fluorometholone Nanoparticles and Bromfenac/Levofloxacin Solution Improve Drug Corneal Penetration |
| title_short |
Fixed-Combination Eye Drops Based on Fluorometholone Nanoparticles and Bromfenac/Levofloxacin Solution Improve Drug Corneal Penetration |
| title_full |
Fixed-Combination Eye Drops Based on Fluorometholone Nanoparticles and Bromfenac/Levofloxacin Solution Improve Drug Corneal Penetration |
| title_fullStr |
Fixed-Combination Eye Drops Based on Fluorometholone Nanoparticles and Bromfenac/Levofloxacin Solution Improve Drug Corneal Penetration |
| title_full_unstemmed |
Fixed-Combination Eye Drops Based on Fluorometholone Nanoparticles and Bromfenac/Levofloxacin Solution Improve Drug Corneal Penetration |
| title_sort |
fixed-combination eye drops based on fluorometholone nanoparticles and bromfenac/levofloxacin solution improve drug corneal penetration |
| publisher |
Dove Medical Press |
| publishDate |
2021 |
| url |
https://doaj.org/article/037b0009a2d84b57b72ec4ccb7b4c5cd |
| work_keys_str_mv |
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