Self-nanoemulsifying drug delivery system to improve transcorneal permeability of voriconazole: in-vivo studies Bakoliarisoa Nivomalala Voahangy Rasoanirina a , Mohamed Ali Lassoued a , Karim Miladi a , Zoarilala Razafindrakoto b , Raja Cha^ abane-Banaoues c , David Ramanitrahasimbola b,d , Muriel Cornet e and Souad Sfar a a Laboratory of Pharmaceutical, Chemical and Pharmacological Drug Development LR12ES09, Faculty of Pharmacy, University of Monastir, Monastir, Tunisia, b Laboratory of Applied Pharmacognosy, Institut Malgache de Recherches Appliqu ees, Fondation Albert et Suzanne RAKOTO- RATSIMAMANGA, Antananarivo, Madagascar, c Laboratory of Medical and Molecular Parasitology-Mycology, LR12ES08 (LP3M), Faculty of Pharmacy, University of Monastir, Monastir, Tunisia, d Pharmacy Department, Faculty of Medicine, University of Antananarivo, Antananarivo, Madagascar and e CNRS, CHU Grenoble Alpes, Grenoble INP, TIMC-IMAG, University of Grenoble Alpes, Grenoble, France Keywords minimum inhibitory concentration aqueous humour; mycotic keratitis; ocular delivery; self-nanoemulsifying drug delivery system; voriconazole Correspondence Mohamed Ali Lassoued, Laboratory of Pharmaceutical, Chemical and Pharmacological Drug Development LR12ES09, Faculty of Pharmacy, University of Monastir, 01 rue Avicenne, 5000 Monastir, Tunisia. E-mail: lassoued98@yahoo.fr Received December 20, 2019 Accepted March 8, 2020 doi: 10.1111/jphp.13265 Abstract Objective This study investigates the effectiveness of self-nanoemulsifying drug delivery system (SNEDDS) in improving voriconazole transcorneal permeability. Methods Voriconazole-SNEDDS was prepared with isopropyl myristate, PEG 400, Tween 80 â and Span 80 â and was subjected for physicochemical characteri- zation after reconstitution with NaCl 0.9% (1/9; v/v). In-vitro antifungal activity was assessed and compared with the marketed formulation. In-vivo studies, namely ocular irritation test via modified Draize test and pharmacokinetic study, were investigated using rabbit as animal model. Key findings Voriconazole-SNEDDS presented a droplet size of 21.353 Æ 0.065 nm, a polydispersity index of 0.123 Æ 0.003, a pH of 7.205 Æ 0.006 and an osmolarity of 342.667 Æ 2.517 mOsmol/l after reconstitution with NaCl 0.9%. Voriconazole-SNEDDS minimum inhibitory concentration (MIC 90 ) was similar to the one of marketed formulation for Candida species while it was significantly lower (P < 0.001) for Aspergillus fumigatus. Draize test revealed that Voricona- zole-SNEDDS was safe for ocular administration. Voriconazole maximum con- centration (5.577 Æ 0.852 μg/ml) from SNEDDS was higher than marketed formulation (C max = 4.307 Æ 0.623 μg/ml), and the T max was delayed to 2 h. The area under the concentration–time curve value of Voriconazole-SNEDDS was improved by 2.419-fold. Conclusion Our results suggest that SNEDDS is a promising carrier for voriconazole ocular delivery and this encourages further clinical studies. Introduction Voriconazole (VCZ) has a wide spectrum of activity against resistant fungal species associated with keratitis. This sec- ond-generation triazole agent is prescribed for the treat- ment of recalcitrant fungal keratitis. [1] However, VCZ is commercially available in only oral and intravenous forms. The latter is linked to significant adverse reactions such as hepatotoxicity. [2] Furthermore, the minimum recom- mended treatment period is between 6 weeks (corneal epithelium damage) to several months (deeper layers of the cornea damage). [3] Intrastromal, intracameral and intravit- real injections of VCZ are often prescribed due to the low ocular bioavailability of topical ophthalmic solution as well as adverse effects following systemic administration. Besides being painful, this ophthalmic delivery approach requires trained professionals and special infrastructure. [2] Topical non-invasive route constitutes the most com- mon route to treat anterior ocular diseases especially those that needs extended duration such as fungal keratitis. [4] Topical eye drop is also economic, safe and easy to admin- ister leading a good patient compliance. However, VCZ eye drop solution 1% (w/v) is prepared extemporaneously from intravenous formulation (lyophilized powder of cyclodextrin–VCZ complex). It is worth mentioning that VCZ is a lipophilic molecule with low solubility. Hence, to © 2020 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 72 (2020), pp. 889–896 889 Research Paper Downloaded from https://academic.oup.com/jpp/article/72/7/889/6122156 by guest on 03 July 2022