Yousry, CarolEl-Gazayerly, Omaima N.Basalious, Emad B.Salem, Heba M.Zikry, Pakinam M.2020-02-032020-02-031/27/2020Thomas, P.A. Fungal infections of the cornea (Open Access) (2003) Eye, 17 (8), pp. 852-862. Cited 257 times. http://www.nature.com/eye/index.html doi: 10.1038/sj.eye.6700557 View at Publisher 2 Kalkanci, A., Ozdek, S. Ocular fungal infections (2011) Current Eye Research, 36 (3), pp. 179-189. Cited 44 times. doi: 10.3109/02713683.2010.533810 View at Publisher 3 O'Brien, T.P. Therapy of ocular fungal infections (1999) Ophthalmology Clinics of North America, 12 (1), pp. 33-50. Cited 31 times. http://www.elsevier.com/inca/publications/store/6/2/3/1/6/8/index.htt doi: 10.1016/S0896-1549(05)70147-4 View at Publisher 4 Kakkar, S., Kaur, I.P. Spanlastics-A novel nanovesicular carrier system for ocular delivery (2011) International Journal of Pharmaceutics, 413 (1-2), pp. 202-210. Cited 57 times. doi: 10.1016/j.ijpharm.2011.04.027 View at Publisher 5 Lakhundi, S., Siddiqui, R., Khan, N.A. Pathogenesis of microbial keratitis (2017) Microbial Pathogenesis, 104, pp. 97-109. Cited 38 times. http://www.elsevier.com/inca/publications/store/6/2/2/9/1/5/index.htt doi: 10.1016/j.micpath.2016.12.013 View at Publisher 6 Peyton, L.R., Gallagher, S., Hashemzadeh, M. Triazole antifungals: A review (2015) Drugs of Today, 51 (12), pp. 705-718. Cited 55 times. https://journals.prous.com/journals/servlet/xmlxsl/dot/20155112/pdf/dt510705.pdf?p_JournalId=4&p_refId=2421058&p_IsPs=N doi: 10.1358/dot.2015.51.12.2421058 View at Publisher 7 Tolman, E.L., Isaacson, D.M., Rosenthale, M.E., McGuire, J.L., Van Cutsem, J., Borgers, M., Van den Bossche, H. Anticandidal activities of terconazole, a broad-spectrum antimycotic (Open Access) (1986) Antimicrobial Agents and Chemotherapy, 29 (6), pp. 986-991. Cited 14 times. doi: 10.1128/AAC.29.6.986 View at Publisher 8 Van Cutsem, J., Van Gerven, F., Zaman, R., Janssen, P.A.J. Terconazole – A new broad-spectrum antifungal (1983) Chemotherapy, 29 (5), pp. 322-331. Cited 22 times. doi: 10.1159/000238215 View at Publisher 9 Schulman, J.A., Peyman, G.A., Dietlein, J., Fiscella, R., Colantino, B. Ocular toxicity after intravitreal injection of terconazole. (1989) Annals of ophthalmology, 21 (9), pp. 345-347. Cited 3 times. 10 Le Bourlais, C., Acar, L., Zia, H., Sado, P.A., Needham, T., Leverge, R. Ophthalmic drug delivery systems - Recent advances (1998) Progress in Retinal and Eye Research, 17 (1), pp. 33-58. Cited 504 times. doi: 10.1016/S1350-9462(97)00002-5 View at Publisher 11 Ameeduzzafar, Ali, J., Bhatnagar, A., Kumar, N., Ali, A. Chitosan nanoparticles amplify the ocular hypotensive effect of cateolol in rabbits (2014) International Journal of Biological Macromolecules, 65, pp. 479-491. Cited 36 times. www.elsevier.com/locate/ijbiomac doi: 10.1016/j.ijbiomac.2014.02.002 View at Publisher 12 Hironaka, K., Inokuchi, Y., Tozuka, Y., Shimazawa, M., Hara, H., Takeuchi, H. Design and evaluation of a liposomal delivery system targeting the posterior segment of the eye (2009) Journal of Controlled Release, 136 (3), pp. 247-253. Cited 73 times. doi: 10.1016/j.jconrel.2009.02.020 View at Publisher 13 Aburahma, M.H. Bile salts-containing vesicles: promising pharmaceutical carriers for oral delivery of poorly water-soluble drugs and peptide/protein-based therapeutics or vaccines (2016) Drug Delivery, 23 (6), pp. 1847-1867. Cited 28 times. doi: 10.3109/10717544.2014.976892 View at Publisher 14 Janga, K.Y., Tatke, A., Balguri, S.P., Lamichanne, S.P., Ibrahim, M.M., Maria, D.N., Jablonski, M.M., (...), Majumdar, S. Ion-sensitive in situ hydrogels of natamycin bilosomes for enhanced and prolonged ocular pharmacotherapy: in vitro permeability, cytotoxicity and in vivo evaluation (Open Access) (2018) Artificial Cells, Nanomedicine and Biotechnology, 46 (sup1), pp. 1039-1050. Cited 9 times. http://www.tandfonline.com/loi/ianb20#.VmugQbfovcs doi: 10.1080/21691401.2018.1443117 View at Publisher 15 Abdelbary, G. Ocular ciprofloxacin hydrochloride mucoadhesive chitosan-coated liposomes (2011) Pharmaceutical Development and Technology, 16 (1), pp. 44-56. Cited 74 times. doi: 10.3109/10837450903479988 View at Publisher 16 Shamma, R.N., Elsayed, I. Transfersomal lyophilized gel of buspirone HCl: Formulation, evaluation and statistical optimization (2013) Journal of Liposome Research, 23 (3), pp. 244-254. Cited 39 times. doi: 10.3109/08982104.2013.801489 View at Publisher 17 Basha, M., Abd El-Alim, S.H., Shamma, R.N., Awad, G.E.A. Design and optimization of surfactant-based nanovesicles for ocular delivery of Clotrimazole (2013) Journal of Liposome Research, 23 (3), pp. 203-210. Cited 37 times. doi: 10.3109/08982104.2013.788025 View at Publisher 18 Zeisig, R., Shimada, K., Hirota, S., Arndt, D. Effect of sterical stabilization on macrophage uptake in vitro and on thickness of the fixed aqueous layer of liposomes made from alkylphosphocholines (Open Access) (1996) Biochimica et Biophysica Acta - Biomembranes, 1285 (2), pp. 237-245. Cited 81 times. doi: 10.1016/S0005-2736(96)00167-8 View at Publisher 19 Gonnissen, Y., Gonçalves, S.I.V., De Geest, B.G., Remon, J.P., Vervaet, C. Process design applied to optimise a directly compressible powder produced via a continuous manufacturing process (2008) European Journal of Pharmaceutics and Biopharmaceutics, 68 (3), pp. 760-770. Cited 39 times. doi: 10.1016/j.ejpb.2007.09.007 View at Publisher 20 Liu, Z., Li, J., Nie, S., Guo, H., Pan, W. Effects of Transcutol P on the corneal permeability of drugs and evaluation of its ocular irritation of rabbit eyes (2006) Journal of Pharmacy and Pharmacology, 58 (1), pp. 45-50. Cited 38 times. doi: 10.1211/jpp.58.1.0006 View at Publisher 21 Zhao, Y., Wang, C., Chow, A.H.L., Ren, K., Gong, T., Zhang, Z., Zheng, Y. Self-nanoemulsifying drug delivery system (SNEDDS) for oral delivery of Zedoary essential oil: Formulation and bioavailability studies (2010) International Journal of Pharmaceutics, 383 (1-2), pp. 170-177. Cited 154 times. www.elsevier.com/locate/ijpharm doi: 10.1016/j.ijpharm.2009.08.035 View at Publisher 22 Xue, X., Cao, M., Ren, L., Qian, Y., Chen, G. Preparation and Optimization of Rivaroxaban by Self-Nanoemulsifying Drug Delivery System (SNEDDS) for Enhanced Oral Bioavailability and No Food Effect (2018) AAPS PharmSciTech, 19 (4), pp. 1847-1859. Cited 11 times. http://www.springerlink.com/content/1530-9932/ doi: 10.1208/s12249-018-0991-6 View at Publisher 23 Yousry, C., Zikry, P.M., Basalious, E.B., El-Gazayerly, O.N. Self-nanoemulsifying system optimization for higher terconazole solubilization and non-irritant ocular administration Adv Pharm Bull in press 24 Beg, S., Swain, S., Singh, H.P., Patra, C.N., Rao, M.B. Development, optimization, and characterization of solid self-nanoemulsifying drug delivery systems of valsartan using porous carriers (2012) AAPS PharmSciTech, 13 (4), pp. 1416-1427. Cited 92 times. doi: 10.1208/s12249-012-9865-5 View at Publisher 25 Wu, T.G., Wilhelmus, K.R., Mitchell, B.M. Experimental keratomycosis in a mouse model (Open Access) (2003) Investigative Ophthalmology and Visual Science, 44 (1), pp. 210-216. Cited 110 times. doi: 10.1167/iovs.02-0446 View at Publisher 26 Habib, F.S., Fouad, E.A., Abdel-Rhaman, M.S., Fathalla, D. Liposomes as an ocular delivery system of fluconazole: In-vitro studies (2010) Acta Ophthalmologica, 88 (8), pp. 901-904. Cited 49 times. doi: 10.1111/j.1755-3768.2009.01584.x View at Publisher 27 Khan, R., Irchhaiya, R. Niosomes: a potential tool for novel drug delivery (2016) Journal of Pharmaceutical Investigation, 46 (3), pp. 195-204. Cited 21 times. http://www.springer.com/biomed/journal/40005 doi: 10.1007/s40005-016-0249-9 View at Publisher 28 Niu, M., Tan, Y., Guan, P., Hovgaard, L., Lu, Y., Qi, J., Lian, R., (...), Wu, W. Enhanced oral absorption of insulin-loaded liposomes containing bile salts: A mechanistic study (2014) International Journal of Pharmaceutics, 460 (1-2), pp. 119-130. Cited 73 times. doi: 10.1016/j.ijpharm.2013.11.028 View at Publisher 29 Rajput, T., Chauhan, M.K. Bilosome: a bile salt based novel carrier system gaining interest in pharmaceutical research (2017) J Drug Deliv Sci Technol., 7 (5), pp. 4-16. Cited 4 times. 30 Aksungur, P., Demirbilek, M., Denkbaş, E.B., Vandervoort, J., Ludwig, A., Ünlü, N. Development and characterization of Cyclosporine A loaded nanoparticles for ocular drug delivery: Cellular toxicity, uptake, and kinetic studies (2011) Journal of Controlled Release, 151 (3), pp. 286-294. Cited 107 times. doi: 10.1016/j.jconrel.2011.01.010 View at Publisher 31 Fetih, G. Fluconazole-loaded niosomal gels as a topical ocular drug delivery system for corneal fungal infections (2016) Journal of Drug Delivery Science and Technology, 35, pp. 8-15. Cited 14 times. http://www.editionsdesante.fr/category.php?id_category=48 doi: 10.1016/j.jddst.2016.06.002 View at Publisher 32 Singh, C.H., Jain, C., Kumar, B.N. Formulation, characterization, stability and invitro evaluation of nimesulide niosomes (2011) Pharmacophore., 3 (3), pp. 168-185. Cited 20 times. 33 Wilkhu, J.S., McNeil, S.E., Anderson, D.E., Perrie, Y. Characterization and optimization of bilosomes for oral vaccine delivery (2013) Journal of Drug Targeting, 21 (3), pp. 291-299. Cited 27 times. doi: 10.3109/1061186X.2012.747528 View at Publisher 34 Guan, P., Lu, Y., Qi, J., Niu, M., Lian, R., Hu, F., Wu, W. Enhanced oral bioavailability of cyclosporine A by liposomes containing a bile salt. (2011) International journal of nanomedicine, 6, pp. 965-974. Cited 94 times. 35 Müller, R.H., Jacobs, C., Kayser, O. Nanosuspensions as particulate drug formulations in therapy: Rationale for development and what we can expect for the future (2001) Advanced Drug Delivery Reviews, 47 (1), pp. 3-19. Cited 1016 times. www.elsevier.com/locate/drugdeliv doi: 10.1016/S0169-409X(00)00118-6 View at Publisher 36 Dai, Y., Zhou, R., Liu, L., Lu, Y., Qi, J., Wu, W. Liposomes containing bile salts as novel ocular delivery systems for tacrolimus (FK506): In vitro characterization and improved corneal permeation (Open Access) (2013) International Journal of Nanomedicine, 8, pp. 1921-1933. Cited 74 times. http://www.dovepress.com/getfile.php?fileID=16081 doi: 10.2147/IJN.S44487 View at Publisher 37 Salama, H.A., Mahmoud, A.A., Kamel, A.O., Abdel Hady, M., Awad, G.A.S. Brain delivery of olanzapine by intranasal administration of transfersomal vesicles (2012) Journal of Liposome Research, 22 (4), pp. 336-345. Cited 57 times. doi: 10.3109/08982104.2012.700460 View at Publisher 38 Jovanović, A.A., Balanč, B.D., Ota, A., Ahlin Grabnar, P., Djordjević, V.B., Šavikin, K.P., Bugarski, B.M., (...), Poklar Ulrih, N. Comparative Effects of Cholesterol and β-Sitosterol on the Liposome Membrane Characteristics (2018) European Journal of Lipid Science and Technology, 120 (9), art. no. 1800039. Cited 5 times. http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1438-9312 doi: 10.1002/ejlt.201800039 View at Publisher 39 Basalious, E.B., Shawky, N., Badr-Eldin, S.M. SNEDDS containing bioenhancers for improvement of dissolution and oral absorption of lacidipine. I: Development and optimization (2010) International Journal of Pharmaceutics, 391 (1-2), pp. 203-211. Cited 163 times. doi: 10.1016/j.ijpharm.2010.03.008 View at Publisher 40 Basalious, E.B., El-Sebaie, W., El-Gazayerly, O. Application of pharmaceutical QbD for enhancement of the solubility and dissolution of a class II BCS drug using polymeric surfactants and crystallization inhibitors: Development of controlled-release tablets (2011) AAPS PharmSciTech, 12 (3), pp. 799-810. Cited 47 times. doi: 10.1208/s12249-011-9646-6 View at Publisher 41 Balakumar, K., Raghavan, C.V., selvan, N.T., prasad, R.H., Abdu, S. Self nanoemulsifying drug delivery system (SNEDDS) of Rosuvastatin calcium: Design, formulation, bioavailability and pharmacokinetic evaluation (2013) Colloids and Surfaces B: Biointerfaces, 112, pp. 337-343. Cited 99 times. doi: 10.1016/j.colsurfb.2013.08.025 View at Publisher 42 Singh, S.K., Prasad Verma, P.R., Razdan, B. Glibenclamide-loaded self-nanoemulsifying drug delivery system: Development and characterization (2010) Drug Development and Industrial Pharmacy, 36 (8), pp. 933-945. Cited 57 times. http://informahealthcare.com/loi/ddi doi: 10.3109/03639040903585143 View at Publisher 43 Behrens-Baumann, W., Klinge, B., Rüchel, R. Topical fluconazole for experimental Candida keratitis in rabbits (Open Access) (1990) British Journal of Ophthalmology, 74 (1), pp. 40-42. Cited 34 times. doi: 10.1136/bjo.74.1.402190393Xhttps://doi.org/10.1007/s13346-020-00716-5https://t.ly/7O3XbSCOPUSOcular drug administration is usually problematic and suffers low bioavailability due to several physiological and biological factors that hinder their effective treatment. Terconazole (TZ) is considered as one of the effective ocular antifungal agents that is usually administrated intravitreally for higher efficacy. The aim of the work in this study is to formulate a TZ-loaded ocular drug delivery system with high efficiency and good tolerability. First, TZ-loaded bile-based nanovesicles (BBNV) were prepared and the formulation variables (namely, Span 60, cholesterol, and sodium deoxycholate levels) were optimized based on the results of the entrapment efficiency (EE%), particle size (PS), and zeta potential (ZP) using Box-Behnken statistical design. The optimized system was formulated using 73.59 mg Span 60, 1.28 mg cholesterol, and 3.11 mg sodium deoxycholate. The formulated system showed vesicles with PS of 526 nm, − 42.2 mV ZP, and 93.86% EE%. TZ release, cellular uptake, and cytotoxicity of the optimized system were evaluated in vitro. In addition, in vivo assessment of its safety was conducted histopathologically and via ocular irritation test to ensure the ocular tolerance of the system. Afterwards, the optimized TZ-loaded BBNV was integrated into a self-nanoemulsifying system (SNES) to allow faster TZ release for immediate antifungal effect, enhanced ocular residence, and improved ocular permeation. TZ release study revealed more than 2 folds increment in drug release rate from the integrated system compared to BBNV alone. Finally, this integrated system was assessed for its antifungal activity in vivo where it demonstrated higher antifungal activity against induced Candida albicans infection. [Figure not available: see fulltext.]. © 2020, Controlled Release Society.en-USTerconazoleOcularHistopathologyCellular uptakeCandida albicansBilosomesArticlehttps://doi.org/10.1007/s13346-020-00716-5