Development and characterization of optimized sustained release voriconazole-loaded chitosan nanoparticles for ocular delivery

Document Type : Research Paper


1 Tehran University of Medical Sciences, International Campus, Tehran, Iran

2 Chemical Engineering Department, Varamin-Pishva Branch, Islamic Azad University, Varamin, Iran

3 School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

4 Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

5 Chemistry and Chemical Engineering Research Center of Iran, Tehran, Iran


Voriconazole is an approved antifungal agent belonging to the triazole family. It is generally used for treating aggressive fungal infections such as invasive candidiasis or aspergillosis, as well as certain fungal infections, in immunocompromised patients. Voriconazole has an oral bioavailability of 96%, and patients can receive the medication either by oral or parenteral routes. To fabricate a topical ocular voriconazole delivery system, we prepared voriconazole-loaded chitosan nanoparticles by ionic gelation of chitosan with the addition of sodium tripolyphosphate (TPP). Three chitosan polymers with different molecular weights were tested by varying chitosan and TPP concentrations, and the produced nanoparticles were characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and x-ray powder diffraction (XRD). The obtained data was presented into a Box-Behnken design, which showed a set of optimum parameters that would yield an optimized formulation with the most favourable properties. Subsequently, the optimized formulation was synthesized, and the voriconazole release from this formulation was monitored over 48 hr. Results showed the drug-loaded nanoparticles have high drug loading, show no burst effect, and sustain drug release for up to 48 hr. Therefore, this formulation is a potentially efficient ocular delivery system for voriconazole.

Graphical Abstract

Development and characterization of optimized sustained release voriconazole-loaded chitosan nanoparticles for ocular delivery


  • Particle size of nanoparticles were reduced by decreasing concentration of chitosan at constant pH.
  • At constant pH, by increasing the percentage of TPP from 5 to 20%, the EE% was raised dramatically.
  • The nanoparticles had a high thermal stability that indicated well-establishment of structure.
  • The release pattern indicated a very slow release of drug at each point of time from the nanoparticles.


[1] H. Mollabagher, S. Taheri, M. Majid Mojtahedi, S. Seyedmousavi, Cu-metal organic frameworks (Cu-MOF) as an environment-friendly and economical catalyst for one pot synthesis of tacrine derivatives, RSC Adv. 10 (2020) 1995-2003. 
[2] H. Mollabagher, S. Taheri, An efficient method for the synthesis of neuroprotective drug riluzole, 20th Iranian chemical congress, Iran, 2018. 
[3] G. Mohammadi Ziarani, H. Mollabagher, N. Lashgari, A. Badiei, One-pot solvent-free synthesis of pyranonaphthoquinone-fused spirooxindoles catalyzed by SBA-IL, Sci. Iran. 25 (2018) 3295-304.
[4] G. Mohammadi Ziarani, H. Mollabagher, P.  Gholamzadeh, A. Badiei, F. Yazdian, Synthesis of the biologically active henna based benzochromene derivatives using ionic liquid functionalized SBA-15 as a nanoreactor, Iranian J. Catal. 8 (2018 ) 59-67. 
[5] S.Y. Afsar, G.M. Ziarani, H. Mollabagher, P. Gholamzadeh, A. Badiei, A.A. Soorki, Application of SBA-Pr-SO3H in the synthesis of 2, 3-dihydroquinazoline-4 (1H)-ones: Characterization, UV–Vis investigations and DFT studies, J. Iranian Chem. Soc. 14 (2017) 577-583. 
[6] T. Ahmadi, G.M. Ziarani, P. Gholamzadeh, H. Mollabagher, Recent advances in asymmetric multicomponent reactions (AMCRs), Tetrahedron-Asymmetry, 28 (2017) 708-724. 
[7] D. Al-Badriyeh, C.F. Neoh, K. Stewart, D.C. Kong, Clinical utility of voriconazole eye drops in ophthalmic fungal keratitis, Clinical Ophthalmology (Auckland, NZ) 4 (2010) 391-405. 
[8] S. Hariprasad, W. Mieler,T. Lin, W. Sponsel, J. Graybill, Voriconazole in the treatment of fungal eye infections: a review of current literature, Brit. J. Ophthalmol. 92 (2008) 871-878. 
[9] U.V. Jurkunas, D.P. Langston, K. Colby, Use of voriconazole in the treatment of fungal keratitis, Int. Ophthalmol. Clin. 47 (2007) 47-59. 
[10] K. Khoshnevisan, H. Maleki, H. Samadian, S. Shahsavari, M.H. Sarrafzadeh, B. Larijani, et al., Cellulose acetate electrospun nanofibers for drug delivery systems: Applications and recent advances, Carbohyd. Polym. 198 (2018) 131-141. 
[11] S. Shahsavari, L.R. Shirmard, M. Amini, F.A. Dokoosh, Application of artificial neural networks in the design and optimization of a nanoparticulate fingolimod delivery system based on biodegradable Poly (3-Hydroxybutyrate-Co-3-Hydroxyvalerate), J. Pharm. Sci. 106 (2017) 176-182. 
[12] S. Seifirad, H. Karami, S. Shahsavari, F. Mirabasi, F. Dorkoosh, Design and characterization of mesalamine loaded nanoparticles for controlled delivery system, Nanomed. Res. J. 1 (2016) 97-106. 
[13] S. Shahsavari, E. Vasheghani-Farahani, M. Ardjmand, F. Abedin Dorkoosh, Modeling of drug released from acyclovir nanoparticles based on artificial neural networks, Lett. Drug Des. Discov. 11 (2014) 174-183. 
[14] S. Shahsavari, E. Vasheghani-Farahani, M. Ardjmand, F. Abedin Dorkoosh, Design and characterization of acyclovir loaded nanoparticles for controlled delivery system, Curr. Nanosci. 10 (2014) 521-531.
[15] S. Shahsavari, G. Bagheri, R. Mahjub, R. Bagheri, M. Radmehr, M. Rafiee-Tehrani, et al., Application of artificial neural networks for optimization of preparation of insulin nanoparticles composed of quaternized aromatic derivatives of chitosan, Drug Res. 64 (2014) 151-158. 
[16] A.J. Ullmann, Review of the safety, tolerability, and drug interactions of the new antifungal agents caspofungin and voriconazole, Curr. Med. Res. Opin. 19 (2003) 263-271. 
[17] A. Stewart, R. Powles, M. Hewetson, J. Antrum, C. Richardson, J. Mehta, Costs of antifungal prophylaxis after bone marrow transplantation, Pharmacoeconomics, 8 (1995) 350-361. 
[18] W. Sponsel, N. Chen, D. Dang, G. Paris, J. Graybill, L.K. Najvar, et al., Topical voriconazole as a novel treatment for fungal keratitis, Antimicrob. Agents Ch. 50 (2006) 262-268. 
[19] A.B. Clode, J.L. Davis, J. Salmon, T.M. Michau, B.C. Gilger, Evaluation of concentration of voriconazole in aqueous humor after topical and oral administration in horses, Am. J. Vet. Res. 67 (2006) 296-301. 
[20] D. Lau, M. Fedinands, L. Leung, R. Fullinfaw, D. Kong, G. Davies, et al., Penetration of voriconazole, 1%, eyedrops into human aqueous humor: a prospective open-label study, Arch. Ophthalmol.-Chic 126 (2008) 343-346. 
[21] G.A. Vemulakonda, S.M. Hariprasad, W.F. Mieler, R.A. Prince, G.K. Shah, R.N. Van Gelder, Aqueous and vitreous concentrations following topical administration of 1% voriconazole in humans, Arch. Ophthalmol.-Chic 126 (2008) 18-22. 
[22] N. Sharma, P. Agarwal, R. Sinha, J.S. Titiyal, T. Velpandian, R.B. Vajpayee, Evaluation of intrastromal voriconazole injection in recalcitrant deep fungal keratitis: case series, Brit. J. Ophthalmol. 95 (2011) 1735-1737. 
[23] K.H. Kim, M.J. Kim, H. Tchah, Management of fungal ocular infection with topical and intracameral voriconazole,  J. Korean Ophthalmol. Soc. 49 (2008) 1054-1060. 
[24] S. Malhotra, A. Khare, K. Grover, I. Singh, P. Pawar, Design and evaluation of voriconazole eye drops for the treatment of fungal keratitis, J. Pharm.  (Cairo) 2014 (2014) 490595. 
[25] W. Xiang-Gen, Y. Li-Na, X. Meng, J. Hao-Ran, Anti-infectious activity of intravitreal injectable voriconazole microspheres on experimental rabbit fungal endophthalmitis caused by Aspergillus fumigatus, J. Pharm. Sci. 100 (2011) 1745-1759. 
[26] R. Kumar, V. Sinha, Preparation and optimization of voriconazole microemulsion for ocular delivery, Colloid. Surface. B, 117 (2014) 82-88. 
[27] R. Kumar, V. Sinha, Fabrication of voriconazole solid lipid nanoparticles for effective ocular delivery, Value Health, 17 (2014) A613. 
[28] H. Peng, X. Liu, G. Lv, B. Sun, Q. Kong, D. Zhai, Q. Wang, W. Zhao, G. wang et al., Voriconazole into PLGA nanoparticles: Improving agglomeration and antifungal efficacy, Int. J. Pharm. 352 (2008) 29-35. 
[29] P. Pawar, H. Kashyap, S. Malhotra, R. Sindhu, Hp-β-CD-voriconazole in situ gelling system for ocular drug delivery: in vitro, stability, and antifungal activities assessment, Biomed. Res. Int. 2013 (2013) 341218. 
[30] A.J. Wagstaff, D. Faulds, K.L.Goa, Aciclovir. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic efficacy, Drugs, 47 (1994) 153-205. 
[31] P. Calvo, C. Remuñan-López, J.L. Vila-Jato, M.J. Alonso, Chitosan and chitosan/ethylene oxide-propylene oxide block copolymer nanoparticles as novel carriers for proteins and vaccines, Pharm. Res.  14 (1997) 1431-1436. 
[32] Ü. Açıkel, M. Erşan, Y.S. Açıkel, Optimization of critical medium components using response surface methodology for lipase production by Rhizopus delemar, Food Bioprod. Process. 88 (2010) 31-39.
Volume 7, Issue 1
May 2021
Pages 1-10
  • Receive Date: 05 March 2021
  • Revise Date: 08 September 2021
  • Accept Date: 07 October 2021
  • First Publish Date: 07 October 2021