Abstract
Lomefloxacin HCl (LF) is a widely used fourth-generation fluoroquinolone antibiotic. Like most drug solutions administered via ocular route, it is usually eliminated by eye protective mechanisms. Chitosan (CS) is a natural polysaccharide polymer with numerous advantages in ocular delivery with, antibacterial, and antifungal properties. The aims were to formulate and optimize LF nanosuspensions (NS) with enhanced antimicrobial activity and prolonged duration using ionic gelation technique. Formulation variables included drug load, CS concentration, crosslinker type (tripolyphosphate and sodium alginate), and concentration. Nanosuspension properties (particle size, zeta potential, polydispersity index, entrapment efficiency, drug release, and permeation through bovine cornea) were evaluated. The artificial neural networks (ANNs) model showed optimum entrapment efficiency of 70.63 % w/w, particle size of 176 ± 0.28 nm, and zeta potential of 13.65 mV. Transmission electron microscopy illustrated the production of well-defined spherical nanoparticles. The nanosuspensions showed prolonged release of LF for more than 8 h and threefold increase in amount permeated through bovine cornea compared to drug solution. Improved antibacterial activity of the nanosuspension was noted where 2- and 3.5-fold decrease in minimum inhibitory concentration (MIC) of drug against Gram-positive and Gram-negative bacteria were observed, respectively. Twofold decrease in minimum bactericidal concentration (MBC) of drug nanosuspension against both types of bacteria was also demonstrated. Histopathological examination showed compatibility of optimized formulation with eye tissues in rabbit model. Therefore, model-optimized LF nanosuspension could be an ideal solution to ocular infections by virtue of their augmented activity, high compatibility, and improved permeability.
Similar content being viewed by others
References
Sultana N, Arayne MS, Furqan H. In vitro availability of lomefloxacin hydrochloride in presence of essential and trace elements. Pak J Pharm Sci. 2005;18:59–65.
Volpe DA. Permeability classification of representative fluoroquinolones by a cell culture method. AAPS Pharm Sci. 2004;6:1–6.
Klosinska-Szmurlo E, Grudzien M, Betlejewska-Kielak K, Plucinski FA, Biernacka J, Mazurek AP. Physico-chemical properties of lomefloxacin, levofloxacin and moxifloxacin relevant to Biopharmaceutics Classification System. Acta Chim Slov. 2014;61:827–34.
Sun J, Sakai S, Tauchi Y, Deguchi Y, Chen J, Zhang R, et al. Determination of lipophilicity of two quinolone antibacterials, ciprofloxacin and grepafloxacin, in the protonation equilibrium. Eur J Pharm Biopharm. 2002;54:51–8.
Volgyi G, Vizseralek G, Takacs-Novak K, Avdeef A, Tam KY. Predicting the exposure and antibacterial activity of fluoroquinolones based on physicochemical properties. Eur J Pharm Sci. 2012;47:21–7.
Mishra GP, Bagui M, Tamboli V, Mitra AK. Recent applications of liposomes in ophthalmic drug delivery. J Drug Deliv. 2011;2011:1–14.
Bucolo C, Maltese A, Drago F, eds. When nanotechnology meets the ocular surface. 2008;325–32.
Raju HB, Goldberg JL, eds. Nanotechnology for ocular therapeutics and tissue repair. 2008;431–6.
Badawi AA, El-Laithy HM, El Qidra RK, El Mofty H. Chitosan based nanocarriers for indomethacin ocular delivery. Arch Pharm Res. 2008;31:1040–9.
de la Fuente M, Ravia M, Paolicelli P, Sanchez A, Seijo BA, Alonso MJ. Chitosan-based nanostructures: a delivery platform for ocular therapeutics. Adv Drug Deliv Rev. 2010;62:100–17.
Kayser O, Lemke A, Hernandez-Trejo N. The impact of nanobiotechnology on the development of new drug delivery systems. Curr Pharm Biotechnol. 2005;6:3–5.
Mainardes RM, Urban MC, Cinto PO, Khalil NM, Chaud MV, Evangelista RC, et al. Colloidal carriers for ophthalmic drug delivery. Curr Drug Targets. 2005;6:363–71.
Ali M, Byrne ME. Challenges and solutions in topical ocular drug-delivery systems. Periodical. Challenges and solutions in topical ocular drug-delivery systems. 2008;1:145–61.
Pignatello R, Puglisi G. Nanotechnology in ophthalmic drug delivery: a survey of recent developments and patenting activity. Recent Pat Nanomedicine. 2011;1:42–54.
Del Amo EM, Urtti A. Current and future ophthalmic drug delivery systems: a shift to the posterior segment. Drug Discov Today. 2008;13:135–43.
Durairaj C, Kadam RS, Chandler JW, Hutcherson SL, Kompella UB. Nanosized dendritic polyguanidilyated translocators for enhanced solubility, permeability, and delivery of gatifloxacin. Invest Ophthalmol Vis Sci. 2010;51:5804–16.
Alonso MJ, Sanchez A. The potential of chitosan in ocular drug delivery. J Pharm Pharmacol. 2003;55:1451–63.
Van der Merwe S, Verhoef J, Verheijden J, Kotze A, Junginger H. Trimethylated chitosan as polymeric absorption enhancer for improved peroral delivery of peptide drugs. Eur J Pharm Biopharm. 2004;58:225–35.
Di Colo G, Zambito Y, Burgalassi S, Nardini I, Saettone M. Effect of chitosan and of N-carboxymethylchitosan on intraocular penetration of topically applied ofloxacin. Int J Pharm. 2004;273:37–44.
Ahuja M, Verma P, Bhatia M. Preparation and evaluation of chitosan-itraconazole co-precipitated nanosuspension for ocular delivery. J Exp Nanosci. 2012;222:1–13.
Qi L, Xu Z, Jiang X, Hu C, Zou X. Preparation and antibacterial activity of chitosan nanoparticles. Carbohydr Res. 2004;339:2693–700.
Ali HS, Blagden N, York P, Amani A, Brook T. Artificial neural networks modelling the prednisolone nanoprecipitation in microfluidic reactors. Eur J Pharm Sci. 2009;37:514–22.
Esmaeilzadeh-Gharedaghi E, Faramarzi MA, Amini MA, Rouholamini Najafabadi A, Rezayat SM, Amani A. Effects of processing parameters on particle size of ultrasound prepared chitosan nanoparticles: an artificial neural networks study. Pharm Dev Technol. 2012;17:638–47.
Amini MA, Faramarzi MA, Mohammadyani D, Esmaeilzadeh-Gharehdaghi E, Amani A. Modeling the parameters involved in preparation of PLA nanoparticles carrying hydrophobic drug molecules using artificial neural networks. J Pharm Innov. 2013;8:111–20.
Motwani SK, Chopra S, Talegaonkar S, Kohli K, Ahmad FJ, Khar RK. Chitosan-sodium alginate nanoparticles as submicroscopic reservoirs for ocular delivery: formulation, optimisation and in vitro characterisation. Eur J Pharm Biopharm. 2008;68:513–25.
Misra R, Acharya S, Dilnawaz F, Sahoo SK. Sustained antibacterial activity of doxycycline-loaded poly (D, L-lactide-co-glycolide) and poly (ε-caprolactone) nanoparticles. Nanomedicine. 2009;4:519–30.
Wu Y, Yang W, Wang C, Hu J, Fu S. Chitosan nanoparticles as a novel delivery system for ammonium glycyrrhizinate. Int J Pharm. 2005;295:235–45.
Liu H, Gao C. Preparation and properties of ionically cross-linked chitosan nanoparticles. Polym Adv Technol. 2009;20:613–9.
Abdelkader H, Ismail S, Kamal A, Alany RG. Design and evaluation of controlled release niosomes and discomes for naltrexone hydrochloride ocular delivery. J Pharm Sci. 2011;100:1833–46.
Gupta AK, Madan S, Majumdar D, Maitra A. Ketorolac entrapped in polymeric micelles: preparation, characterisation and ocular anti-inflammatory studies. Int J Pharm. 2000;209:1–14.
Mitragotri S, Anissimov YG, Bunge AL, Frasch HF, Guy RH, Hadgraft J, Kasting GB, Lane ME, Roberts MS. Mathematical models of skin permeability: an overview. Int J Pharm. 418: 115–29.
Gupta H, Aqil M, Khar R, Ali A, Bhatnagar A, Mittal G. Biodegradable levofloxacin nanoparticles for sustained ocular drug delivery. J Drug Target. 2011;19:409–17.
Luo Q, Zhao J, Zhang X, Pan W. Nanostructured lipid carrier (NLC) coated with chitosan oligosaccharides and its potential use in ocular drug delivery system. Int J Pharm. 2011;403:185–91.
Viertler C, Groelz D, Gündisch S, Kashofer K, Reischauer B, Riegman PHJ, et al. A new technology for stabilization of biomolecules in tissues for combined histological and molecular analyses. J Mol Diagn. 2012;14:458–66.
Colbourn E, Roskilly S, Rowe R, York P. Modelling formulations using gene expression programming—a comparative analysis with artificial neural networks. Eur J Pharm Sci. 2011;44:366–74.
Shao Q, Rowe RC, York P. Comparison of neurofuzzy logic and neural networks in modelling experimental data of an immediate release tablet formulation. Eur J Pharm Sci. 2006;28:394–404.
Ali AMA, Abdelrahim MEA. Modeling and optimization of terbutaline emitted from a dry powder inhaler and influence on systemic bioavailability using data mining technology. J Pharm Innov. 2014;9:38–47.
Kahlmeter G, Brown DF, Goldstein FW, MacGowan AP, Mouton JW, Ӧsterlund A, et al. European harmonization of MIC breakpoints for antimicrobial susceptibility testing of bacteria. J Antimicrob Chemother. 2003;52:145–8.
Ahmed SH, Amin MA, Saafan AE, El-Gendy AO, ul Islam M. Measuring susceptibility of Candida albicans biofilms towards antifungal agents. Der Pharm Lett. 2013;5:376–83.
Rajan M, Raj V. Encapsulation, characterisation and in-vitro release of anti-tuberculosis drug using chitosan-poly ethylene glycol nanoparticles. Int J Pharm Sci. 2012;4:255–9.
Gan Q, Wang T. Chitosan nanoparticle as protein delivery carrier: systematic examination of fabrication conditions for efficient loading and release. Colloids Surf B. 2007;59:24–34.
Boonsongrit Y, Mitrevej A, Mueller BW. Chitosan drug binding by ionic interaction. Eur J Pharm Biopharm. 2006;62:267–74.
Kumar D, Jain N, Gulati N, Nagaich U. Nanoparticles laden in situ gelling system for ocular drug targeting. J Adv Pharm Technol Res. 2013;4:9.
Agnihotri SA, Mallikarjuna NN, Aminabhavi TM. Recent advances on chitosan-based micro-and nanoparticles in drug delivery. J Control Release. 2004;100:5–28.
Zhang J, Chen XG, Li YY, Liu CS. Self-assembled nanoparticles based on hydrophobically modified chitosan as carriers for doxorubicin. Nanomed Nanotechnol. 2007;3:258–65.
Xu Y, Du Y. Effect of molecular structure of chitosan on protein delivery properties of chitosan nanoparticles. Int J Pharm. 2003;250:215–26.
Katas H, Alpar HO. Development and characterisation of chitosan nanoparticles for siRNA delivery. J Control Release. 2006;115:216–25.
Soppimath KS, Aminabhavi TM, Kulkarni AR, Rudzinski WE. Biodegradable polymeric nanoparticles as drug delivery devices. J Control Release. 2001;70:1–20.
Majumdar S, Hippalgaonkar K, Repka MA. Effect of chitosan, benzalkonium chloride and ethylenediaminetetraacetic acid on permeation of acyclovir across isolated rabbit cornea. Int J Pharm. 2008;348:175–8.
De Campos AM, Sanchez A, Alonso MJ. Chitosan nanoparticles: a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to cyclosporin A. Int J Pharm. 2001;224:159–68.
Vega E, Gamisans F, Garcia M, Chauvet A, Lacoulonche F, Egea M. PLGA nanospheres for the ocular delivery of flurbiprofen: drug release and interactions. J Pharm Sci. 2008;97:5306–17.
Benhabiles M, Salah R, Lounici H, Drouiche N, Goosen M, Mameri N. Antibacterial activity of chitin, chitosan and its oligomers prepared from shrimp shell waste. Food Hydrocoll. 2012;29:48–56.
Martinez LR, Mihu MR, Han G, Frases S, Cordero RJ, Casadevall A, et al. The use of chitosan to damage Cryptococcus neoformans biofilms. Biomaterials. 2010;31:669–79.
Fernandes P, Sousa I, Cunha-Silva L, Ferreira M, de Castro B, Feio MJ, et al. Synthesis, characterization and antibacterial studies of a copper (II) levofloxacin ternary complex. J Inorg Biochem. 2014;110:64–71.
Sadeek SA, El-Shwiniy WH, El-Attar MS, Zordok WA. Spectroscopic, structural and antibacterial evaluation of some lomefloxacin metal complexes. Int J Adv Res. 2014;2:158–208.
Singh J, Dutta PK. Preparation, antibacterial and physicochemical behavior of chitosan/ofloxacin complexes. Int J Polym Mater Polym Biomater. 2010;59:793–807.
Acknowledgments
A special acknowledgment is directed to the engineer, Mr. Stephen Roskily, previously working for Intelligensys Ltd., UK, for his help in using of the software (INForm). The authors also want to acknowledge the help given by Dr. Ahmed Osama El-Gendi at Beni-Suef University for help given during the microbiological study.
Ethical Standards
All experiments done in this research on animals were performed according to the laws adopted by the ethical research committee of Beni-Suef University, Egypt.
Conflict of Interest
The authors of this work declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Abdelrahman, A.A., Salem, H.F., Khallaf, R.A. et al. Modeling, Optimization, and In Vitro Corneal Permeation of Chitosan-Lomefloxacin HCl Nanosuspension Intended for Ophthalmic Delivery. J Pharm Innov 10, 254–268 (2015). https://doi.org/10.1007/s12247-015-9224-7
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12247-015-9224-7