Preparation of Thermosensitive Gel for Controlled Release of Levofloxacin and Their Application in the Treatment of Multidrug-Resistant Bacteria

Danilo Antonini Alves, Daisy Machado, Adriana Melo, Rafaella Fabiana Carneiro Pereira, Patrícia Severino, Luciana Maria de Hollanda, Daniele Ribeiro Araújo, Marcelo Lancellotti, Danilo Antonini Alves, Daisy Machado, Adriana Melo, Rafaella Fabiana Carneiro Pereira, Patrícia Severino, Luciana Maria de Hollanda, Daniele Ribeiro Araújo, Marcelo Lancellotti

Abstract

Levofloxacin is a synthetic broad-spectrum antibacterial agent for oral or intravenous administration. Chemically, levofloxacin is the levorotatory isomer (L-isomer) of racemate ofloxacin, a fluoroquinolone antibacterial agent. Quinolone derivatives rapidly and specifically inhibit the synthesis of bacterial DNA. Levofloxacin has in vitro activity against a broad range of aerobic and anaerobic Gram-positive and Gram-negative bacteria. However, formulation of combined poloxamers thermoregulated (as Pluronic® F127) and levofloxacin for use in multiresistant bacterial treatment were poorly described in the current literature. Thus, the aim of the present work is to characterize poloxamers for levofloxacin controlled release and their use in the treatment of multidrug bacterial resistance. Micelles were produced in colloidal dispersions, with a diameter between 5 and 100 nm, which form spontaneously from amphiphilic molecules under certain conditions as concentration and temperature. Encapsulation of levofloxacin into nanospheres showed efficiency and enhancement of antimicrobial activity against Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae when compared with only levofloxacin. Furthermore, all formulations were not cytotoxic for NIH/3T3 cell lineage. In conclusion, poloxamers combined with levofloxacin have shown promising results, better than alone, decreasing the minimal inhibitory concentration of the studied bacterial multiresistance strains. In the future, this new formulation will be used after being tested in animal models in patients with resistant bacterial strains.

Figures

Figure 1
Figure 1
Characteristics of formulations in 25°C and 37°C: (a) polymeric micelles and (b) fluoroquinolone-loaded polymeric micelles.
Figure 2
Figure 2
Levofloxacin liberation across Franz diffusion cells. L (-■-), F1 + L (-●-), F2 + L (-▲-), F3 + L (-▼-), and F4 + L (-◆-) were carried out in Franz diffusion cells for 24 h, and the concentration of levofloxacin permeate was calculated. The results represent the means ± SD.
Figure 3
Figure 3
Effects of polymeric micelles and fluoroquinolone-loaded polymeric micelles on BALB/c 3T3 cell viability. BALB/c 3T3 cells were treated with different concentrations of polymeric micelles (a) and fluoroquinolone-loaded polymeric micelles (b) for 24 h, and cell viability was assessed by MTT reduction assay. The results represent the means ± SD.

References

    1. Khameneh B., Diab R., Ghazvini K., Fazly Bazzaz B. S. Breakthroughs in bacterial resistance mechanisms and the potential ways to combat them. Microbial Pathogenesis. 2016;95:32–42. doi: 10.1016/j.micpath.2016.02.009.
    1. Riley M. A., Robinson S. M., Roy C. M., Dennis M., Liu V., Dorit R. L. Resistance is futile: the bacteriocin model for addressing the antibiotic resistance challenge. Biochemical Society Transactions. 2012;40(6):1438–1442. doi: 10.1042/bst20120179.
    1. Anes J., McCusker M. P., Fanning S., Martins M. The ins and outs of RND efflux pumps in Escherichia coli . Frontiers in Microbiology. 2015;6, article 587 doi: 10.3389/fmicb.2015.00587.
    1. Nischal P. M. First global report on antimicrobial resistance released by the WHO. National Medical Journal of India. 2014;27(4):p. 241.
    1. Aldred K. J., Kerns R. J., Osheroff N. Mechanism of quinolone action and resistance. Biochemistry. 2014;53(10):1565–1574. doi: 10.1021/bi5000564.
    1. Lesher G. Y., Froelich E. J., Gruett M. D., Bailey J. H., Brundage R. P. 1,8-Naphthyridine derivatives. A new class of chemotherapeutic agents. Journal of Medicinal and Pharmaceutical Chemistry. 1962;5(5):1063–1065. doi: 10.1021/jm01240a021.
    1. Emmerson A. M., Jones A. M. The quinolones: decades of development and use. Journal of Antimicrobial Chemotherapy. 2003;51(supplement 1):13–20.
    1. Mitscher L. A. Bacterial topoisomerase inhibitors: quinolone and pyridone antibacterial agents. Chemical Reviews. 2005;105(2):559–592. doi: 10.1021/cr030101q.
    1. Andriole V. T. The quinolones: past, present, and future. Clinical Infectious Diseases. 2005;41(supplement 2):S113–S119. doi: 10.1086/428051.
    1. Stein G. E. The 4-quinolone antibiotics: past, present, and future. Pharmacotherapy. 1988;8(6):301–314. doi: 10.1002/j.1875-9114.1988.tb04088.x.
    1. Baym M., Stone L. K., Kishony R. Multidrug evolutionary strategies to reverse antibiotic resistance. Science. 2016;351(6268) doi: 10.1126/science.aad3292.
    1. Catauro M., Raucci M. G., De Gaetano F., Buri A., Marotta A., Ambrosio L. Sol-gel synthesis, structure and bioactivity of Polycaprolactone/ CaO·SiO2 hybrid material. Journal of Materials Science: Materials in Medicine. 2004;15(9):991–995. doi: 10.1023/b:jmsm.0000042684.13247.38.
    1. Chaibundit C., Ricardo N. M. P. S., Costa F. D. M. L. L., Yeates S. G., Booth C. Micellization and gelation of mixed copolymers P123 and F127 in aqueous solution. Langmuir. 2007;23(18):9229–9236. doi: 10.1021/la701157j.
    1. Anderson V. R., Perry C. M. Levofloxacin: a review of its use as a high-dose, short-course treatment for bacterial infection. Drugs. 2008;68(4):535–565. doi: 10.2165/00003495-200868040-00011.
    1. Noel G. J. A review of levofloxacin for the treatment of bacterial infections. Clinical Medicine Insights. 2009;1:433–458.
    1. Levaquin. Levaquin-Highlights of Prescribing Information. Raritan, NJ, USA: Ortho-McNeil-Janssen Pharmaceuticals; 2016.
    1. Hooper D. C. Mode of action of fluoroquinolones. Drugs. 1999;58(2):6–10. doi: 10.2165/00003495-199958002-00002.
    1. Wieczorek K., Osek J. Antimicrobial resistance mechanisms among campylobacter. BioMed Research International. 2013;2013:12. doi: 10.1155/2013/340605.340605
    1. Guilhelmelli F., Vilela N., Albuquerque P., Derengowski L. D. S., Silva-Pereira I., Kyaw C. M. Antibiotic development challenges: the various mechanisms of action of antimicrobial peptides and of bacterial resistance. Frontiers in Microbiology. 2013;4, article 353 doi: 10.3389/fmicb.2013.00353.
    1. Giedraitiene A., Vitkauskiene A., Naginiene R., Pavilonis A. Antibiotic resistance mechanisms of clinically important bacteria. Medicina. 2011;47(3):137–146.
    1. Pazian G. M., Da Silva Sass Z. F. Resistência bacteriana a antibióticos. Revista Cesumar-Ciências Humanas e Sociais Aplicadas. 2007;11:157–163.
    1. Nebert D. W., Zhang G., Vesell E. S. From human genetics and genomics to pharmacogenetics and pharmacogenomics: past lessons, future directions. Drug Metabolism Reviews. 2008;40(2):187–224. doi: 10.1080/03602530801952864.
    1. Kamboj V. K., Verma P. K. Poloxamers based nanocarriers for drug delivery system. Der Pharmacia Lettre. 2015;7(2):264–269.
    1. Florence A. T., Attwood D. Physicochemical Principles of Pharmacy. London, UK: Macmillan Press; 1998. Polymers and macromolecules.
    1. Moghimi S. M., Hunter A. C. Poloxamers and poloxamines in nanoparticle engineering and experimental medicine. Trends in Biotechnology. 2000;18(10):412–420. doi: 10.1016/s0167-7799(00)01485-2.
    1. Kwon G. S., Okano T. Polymeric micelles as new drug carriers. Advanced Drug Delivery Reviews. 1996;21(2):107–116. doi: 10.1016/S0169-409X(96)00401-2.
    1. Moffitt M., Khougaz K., Eisenberg A. Micellization of ionic block copolymers. Accounts of Chemical Research. 1996;29(2):95–102. doi: 10.1021/ar940080.
    1. Moffitt M., Zhang L., Khougaz K., Eisenberg A. Micellization of ionic block copolymers in three dimensions. Solvents and Self-Organization of Polymers. 1996;327:53–72.
    1. Geethalakshmi R., Sarada D. V. L. Characterization and antimicrobial activity of gold and silver nanoparticles synthesized using saponin isolated from Trianthema decandra L. Industrial Crops and Products. 2013;51:107–115. doi: 10.1016/j.indcrop.2013.08.055.
    1. Gong P., Li H., He X., et al. Preparation and antibacterial activity of Fe3O4@Ag nanoparticles. Nanotechnology. 2007;18(28) doi: 10.1088/0957-4484/18/28/285604.285604
    1. Feng Q. L., Wu J., Chen G. Q., Cui F. Z., Kim T. N., Kim J. O. A mechanistic study of the antibacterial effect of silver ions on Escherichia coli and Staphylococcus aureus . Journal of Biomedical Materials Research. 2000;52(4):662–668. doi: 10.1002/1097-4636(20001215)52:4<662::aid-jbm10>;2-3.
    1. Chana J., Forbes B., Jones S. A. Triggered-release nanocapsules for drug delivery to the lungs. Nanomedicine: Nanotechnology, Biology, and Medicine. 2015;11(1):89–97. doi: 10.1016/j.nano.2014.07.012.
    1. Torchilin V. P. Targeted pharmaceutical nanocarriers for cancer therapy and imaging. The AAPS Journal. 2007;9(2, article 15):E128–E147. doi: 10.1208/aapsj0902015.
    1. Torchilin V. P. Nanocarriers. Pharmaceutical Research. 2007;24(12):2333–2334. doi: 10.1007/s11095-007-9463-5.
    1. Dumortier G., Grossiord J. L., Agnely F., Chaumeil J. C. A review of poloxamer 407 pharmaceutical and pharmacological characteristics. Pharmaceutical Research. 2006;23(12):2709–2728. doi: 10.1007/s11095-006-9104-4.
    1. dos Santos A. C. M., Akkari A. C. S., Ferreira I. R. S., et al. Poloxamer-based binary hydrogels for delivering tramadol hydrochloride: sol-gel transition studies, dissolution-release kinetics, in vitro toxicity, and pharmacological evaluation. International Journal of Nanomedicine. 2015;10:2391–2401. doi: 10.2147/ijn.s72337.
    1. Schmolka I. R. Artificial skin. I. Preparation and properties of pluronic F-127 gels for treatment of burns. Journal of Biomedical Materials Research. 1972;6(6):571–582. doi: 10.1002/jbm.820060609.
    1. De Araujo D. R., Padula C., Cereda C. M. S., et al. Bioadhesive films containing benzocaine: correlation between in vitro permeation and in vivo local anesthetic effect. Pharmaceutical Research. 2010;27(8):1677–1686. doi: 10.1007/s11095-010-0151-5.
    1. NCCLS. M11-A6 Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard. 6th. Philadelphia, Pa, USA: NCCLS; 2004.
    1. Cavalieri S. J. Manual of Antimicrobial Susceptibility Testintg. National Committee for Clinical Laboratory (NCCL); 2005.
    1. Severino P., Chaud M. V., Shimojo A., et al. Sodium alginate-cross-linked polymyxin B sulphate-loaded solid lipid nanoparticles: antibiotic resistance tests and HaCat and NIH/3T3 cell viability studies. Colloids and Surfaces B: Biointerfaces. 2015;129:191–197. doi: 10.1016/j.colsurfb.2015.03.049.
    1. CLSI. Standards NCfCL. Wayne, Pa, USA: NCCLS; 2006. CLSI-Clinical Laboratory Standards Institute, performance standards for minimal inhibitory concentration tests.
    1. Zanin H., Hollanda L. M., Ceragioli H. J., et al. Carbon nanoparticles for gene transfection in eukaryotic cell lines. Materials Science and Engineering: C. 2014;39(1):359–370. doi: 10.1016/j.msec.2014.03.016.
    1. Ferreira T. H., Hollanda L. M., Lancellotti M., De Sousa E. M. B. Boron nitride nanotubes chemically functionalized with glycol chitosan for gene transfection in eukaryotic cell lines. Journal of Biomedical Materials Research—Part A. 2015;103(6):2176–2185. doi: 10.1002/jbm.a.35333.
    1. Hollanda L. M., Lobo A. O., Lancellotti M., Berni E., Corat E. J., Zanin H. Graphene and carbon nanotube nanocomposite for gene transfection. Materials Science and Engineering C. 2014;39(1):288–298. doi: 10.1016/j.msec.2014.03.002.
    1. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Journal of Immunological Methods. 1983;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4.
    1. Machado D., Shishido S. M., Queiroz K. C. S., et al. Irradiated riboflavin diminishes the aggressiveness of melanoma in vitro and in vivo. PLoS ONE. 2013;8, article e54269 doi: 10.1371/journal.pone.0054269.
    1. Li C., Gu J., Mao X. H., Ao H. F., Yang X. Z. Preparation of levofloxacin thermo-sensitive gel and clinical application in the treatment of suppurative otitis media. Acta Oto-Laryngologica. 2014;134(5):468–474. doi: 10.3109/00016489.2013.878473.
    1. Lorente M., Ballano A., Juanes A., Pastor M. A., Cuevas J. Blue-gray pigmentation in trunk and extremities in a 71-year-old man. JAMA Dermatology. 2013;149(9):1111–1112. doi: 10.1001/jamadermatol.2013.4365.
    1. Islan G. A., Dini C., Bartel L. C., Bolzán A. D., Castro G. R. Characterization of smart auto-degradative hydrogel matrix containing alginate lyase to enhance levofloxacin delivery against bacterial biofilms. International Journal of Pharmaceutics. 2015;496(2):953–964. doi: 10.1016/j.ijpharm.2015.10.050.
    1. Paton J. H., Reeves D. S. Clinical features and management of adverse effects of quinolone antibacterials. Drug Safety. 1991;6(1):8–27. doi: 10.2165/00002018-199106010-00002.
    1. Carbon C. Comparison of side effects of levofloxacin versus other fluoroquinolones. Chemotherapy. 2001;47, supplement 3:9–48. doi: 10.1159/000057839.
    1. Turcu I., Bogdan M. Size dependence of molecular self-assembling in stacked aggregates. 1. NMR investigation of ciprofloxacin self-association. The Journal of Physical Chemistry B. 2012;116(22):6488–6498. doi: 10.1021/jp3034215.
    1. Yu L., Ding J. Injectable hydrogels as unique biomedical materials. Chemical Society Reviews. 2008;37(8):1473–1481. doi: 10.1039/b713009k.
    1. Klouda L., Mikos A. G. Thermoresponsive hydrogels in biomedical applications. European Journal of Pharmaceutics and Biopharmaceutics. 2008;68(1):34–45. doi: 10.1016/j.ejpb.2007.02.025.
    1. Klouda L. Thermoresponsive hydrogels in biomedical applications A seven-year update. European Journal of Pharmaceutics and Biopharmaceutics. 2015;97:338–349. doi: 10.1016/j.ejpb.2015.05.017.
    1. Ricardo N. M. P. S., Pinho M. E. N., Yang Z., Attwood D., Booth C. Controlling the gelation of aqueous micellar solutions of ethylene-oxide-based block copoly(oxyalkylene)s. International Journal of Pharmaceutics. 2005;300(1-2):22–31. doi: 10.1016/j.ijpharm.2005.04.023.
    1. Harrison W. J., Aboulgasem G. J., Elathrem F. A. I., et al. Micelles and gels of mixed triblock copoly(oxyalkylene)s in aqueous solution. Langmuir. 2005;21(14):6170–6178. doi: 10.1021/la050297k.
    1. Newby G. E., Hamley I. W., King S. M., Martin C. M., Terrill N. J. Structure, rheology and shear alignment of Pluronic block copolymer mixtures. Journal of Colloid and Interface Science. 2009;329(1):54–61. doi: 10.1016/j.jcis.2008.09.054.
    1. Paavola A., Kilpeläinen I., Yliruusi J., Rosenberg P. Controlled release injectable liposomal gel of ibuprofen for epidural analgesia. International Journal of Pharmaceutics. 2000;199(1):85–93. doi: 10.1016/S0378-5173(00)00376-8.
    1. Paavola A., Yliruusi J., Kajimoto Y., Kalso E., Wahlstrom T., Rosenberg P. Controlled release of lidocaine from injectable gels and efficacy in rat sciatic nerve block. Pharmaceutical Research. 1995;12(12):1997–2002. doi: 10.1023/a:1016264527738.
    1. Paavola A., Yliruusi J., Rosenberg P. Controlled release and dura mater permeability of lidocaine and ibuprofen from injectable poloxamer-based gels. Journal of Controlled Release. 1998;52(1-2):169–178. doi: 10.1016/S0168-3659(97)00206-X.
    1. Park Y.-J., Yong C. S., Kim H.-M., et al. Effect of sodium chloride on the release, absorption and safety of diclofenac sodium delivered by poloxamer gel. International Journal of Pharmaceutics. 2003;263(1-2):105–111. doi: 10.1016/s0378-5173(03)00362-4.
    1. Ricci E. J., Bentley M. V. L. B., Farah M., Bretas R. E. S., Marchetti J. M. Rheological characterization of Poloxamer 407 lidocaine hydrochloride gels. European Journal of Pharmaceutical Sciences. 2002;17(3):161–167. doi: 10.1016/s0928-0987(02)00166-5.
    1. Ricci E. J., Lunardi L. O., Nanclares D. M. A., Marchetti J. M. Sustained release of lidocaine from Poloxamer 407 gels. International Journal of Pharmaceutics. 2005;288(2):235–244. doi: 10.1016/j.ijpharm.2004.09.028.
    1. Chen P.-C., Park Y. J., Chang L.-C., et al. Injectable microparticle-gel system for prolonged and localized lidocaine release. I. In vitro characterization. Journal of Biomedical Materials Research Part A. 2004;70(3):412–419.
    1. Chen P.-C., Kohane D. S., Park Y. J., Bartlett R. H., Langer R., Yang V. C. Injectable microparticle-gel system for prolonged and localized lidocaine release. II. In vivo anesthetic effects. Journal of Biomedical Materials Research—Part A. 2004;70(3):459–466.
    1. Yin Q.-Q., Wu L., Gou M.-L., Qian Z.-Y., Zhang W.-S., Liu J. Long-lasting infiltration anaesthesia by lidocaine-loaded biodegradable nanoparticles in hydrogel in rats. Acta Anaesthesiologica Scandinavica. 2009;53(9):1207–1213. doi: 10.1111/j.1399-6576.2009.02030.x.
    1. Daniels S., Reader S., Berry P., Goulder M. Onset of analgesia with sodium ibuprofen, ibuprofen acid incorporating poloxamer and acetaminophen—a single-dose, double-blind, placebo-controlled study in patients with post-operative dental pain. European Journal of Clinical Pharmacology. 2009;65(4):343–353. doi: 10.1007/s00228-009-0614-y.
    1. Fisher A., Watling M., Smith A., Knight A. Pharmacokinetic comparisons of three nasal fentanyl formulations; pectin, chitosan and chitosan-poloxamer 188. International Journal of Clinical Pharmacology and Therapeutics. 2010;48(2):138–145. doi: 10.5414/cpp48138.
    1. Oshiro A., Da Silva D. C., De Mello J. C., et al. Pluronics F-127/l-81 binary hydrogels as drug-delivery systems: influence of physicochemical aspects on release kinetics and cytotoxicity. Langmuir. 2014;30(45):13689–13698. doi: 10.1021/la503021c.

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