Drug Delivery and Translational Research

, Volume 8, Issue 1, pp 132–139 | Cite as

Ex vivo rabbit cornea diffusion studies with a soluble insert of moxifloxacin

  • María Sebastián-Morelló
  • María Aracely Calatayud-Pascual
  • Vicent Rodilla
  • Cristina Balaguer-Fernández
  • Alicia López-CastellanoEmail author
Original Article


The objective of this research was to develop and evaluate an ocular insert for the controlled drug delivery of moxifloxacin which could perhaps be used in the treatment of corneal keratitis or even bacterial endophthalmitis. We have evaluated the ex vivo ocular diffusion of moxifloxacin through rabbit cornea, both fresh and preserved under different conditions. Histological studies were also carried out. Subsequently, drug matrix inserts were prepared using bioadhesive polymers. The inserts were evaluated for their physicochemical parameters. Ophthalmic ex vivo permeation of moxifloxacin was carried out with the most promising insert. The formulate insert was thin and provided higher ocular diffusion than commercial formulations. Ocular diffusion studies revealed significant differences between fresh and frozen corneas. Histological examinations also showed differences in the thickness of stroma between fresh and frozen corneas. The ophthalmic insert we have developed allows a larger quantity of moxifloxacin to permeate through the cornea than existing commercial formulations of the drug. Ocular delivery of moxifloxacin with this insert could be a new approach for the treatment of eye diseases.


Ophthalmic Drug delivery Moxifloxacin Bacterial endophthalmitis Insert 



Hydroxypropyl methylcellulose 4500




Phosphate buffered solution


Polyethylene glycol


Polyvinylpyrrolidone K30


Compliance with ethical standards

Conflict of interest disclosure

The authors declare that they have no conflict of interest.


  1. 1.
    Souza JG, Dias K, Pereira TA, Bernardi DS, Lopez RFV. Topical delivery of ocular therapeutics: carrier systems and physical methods. J Pharm Pharmacol. 2014;66:507–30.CrossRefPubMedGoogle Scholar
  2. 2.
    Vandervoort J, Ludwig A. Ocular drug delivery: nanomedicine applications. Nanomedicine. 2007;2:11–21.CrossRefPubMedGoogle Scholar
  3. 3.
    Gaudana R, Ananthula HK, Parenky A, Mitra AK. Ocular drug delivery. AAPS J. 2010;12:348–60.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Mundada AS, Shrikhande BK. Design and evaluation of soluble ocular drug insert for controlled release of ciprofloxacin hydrochloride. Drug Dev Ind Pharm. 2006;32:443–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Mundada AS, Shrikhande BK. Formulation and evaluation of ciprofloxacin hydrochloride soluble ocular drug insert. Curr Eye Res. 2008;33:469–75.CrossRefPubMedGoogle Scholar
  6. 6.
    Rathore K, Nema R. Review on ocular inserts. Int J PharmTech Res. 2009;1:164–9.Google Scholar
  7. 7.
    Rathore K, Nema R. An insight into ophthalmic drug delivery system. Int J Pharm Sci Drug Res. 2009;1:1–5.Google Scholar
  8. 8.
    Kampougeris G, Antoniadou A, Kavouklis E, Chryssouli Z, Giamarellou H. Penetration of moxifloxacin into the human aqueous humour after oral administration. Br J Ophthalmol. 2005;89:628–31.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Hariprasad SM, Shah GK, Mieler WF, Feiner L, Blinder KJ, Holekamp NM, et al. Vitreous and aqueous penetration of orally administered moxifloxacin in humans. Arch Ophthalmol. 2006;124:178.Google Scholar
  10. 10.
    Nam KY, Lee SJ, Kim JY. Systemic moxifloxacin in Streptococcus viridans endophthalmitis. Ocul Immunol Inflamm. 2017:1–7.Google Scholar
  11. 11.
    Yannuzzi NA, Si N, Relhan N, et al. Endophthalmitis after clear corneal cataract surgery: outcomes over two decades. Am J Ophthalmol. 2017;174:155–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Woodcock JM, Andrews JM, Boswell FJ, Brenwald NP, Wise R. In vitro activity of BAY 12-8039, a new fluoroquinolone. Antimicrob Agents Chemother. 1997;41:101–6.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Tyson SL, Bailey R, Roman JS, Zhan T, Hark LA, Haller JA. Clinical outcomes after injection of a compounded pharmaceutical for prophylaxis after cataract surgery. Curr Opin Ophthalmol. 2017;28:73–80.CrossRefPubMedGoogle Scholar
  14. 14.
    Langlois M-H, Montagut M, Dubost J-P, Grellet J, Saux M-C. Protonation equilibrium and lipophilicity of moxifloxacin. J Pharm Biomed Anal. 2005;37:389–93.CrossRefPubMedGoogle Scholar
  15. 15.
    Biedenbach DJ, Jones RN. The comparative antimicrobial activity of levofloxacin tested against 350 clinical isolates of streptococci. Diagn Microbiol Infect Dis. 1996;25:47–51.CrossRefPubMedGoogle Scholar
  16. 16.
    Dalhoff A, Petersen U, Endermann R. In vitro activity of BAY 12-8039, a new 8-methoxyquinolone. Chemotherapy. 1996;42:410–25.CrossRefPubMedGoogle Scholar
  17. 17.
    Davis R, Bryson HM. Levofloxacin. Drugs. 1994;47:677–700.CrossRefPubMedGoogle Scholar
  18. 18.
    Pawar PK, Katara R, Majumdar DK. Design and evaluation of moxifloxacin hydrochloride ocular inserts. Acta Pharma. 2012;62:93–104.CrossRefGoogle Scholar
  19. 19.
    Kalevar V. Donor corneae for preservation. A modified dissection technique. Br J Ophthalmol. 1968;52:695.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Majumdar S, Hingorani T, Srirangam R. Evaluation of active and passive transport processes in corneas extracted from preserved rabbit eyes. J Pharm Sci. 2010;99:1921–30.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Fu RC-C, Lidgate DM. In vitro rabbit corneal permeability study of ketorolac, tromethamine, a non-steroidal anti-inflammatory agent. Drug Dev Ind Pharm. 1986;12:2403–30.CrossRefGoogle Scholar
  22. 22.
    Majumdar S, Hingorani T, Srirangam R, Gadepalli RS, Rimoldi JM, Repka MA. Transcorneal permeation of L- and D-aspartate ester prodrugs of acyclovir: delineation of passive diffusion versus transporter involvement. Pharm Res. 2009;26:1261–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Ahuja M, Dhake AS, Majumdar DK. Effect of formulation factors on in-vitro permeation of diclofenac from experimental and marketed aqueous eye drops through excised goat cornea. Yakugaku Zasshi. 2006;126:1369–75.CrossRefPubMedGoogle Scholar
  24. 24.
    Pawar PK, Majumdar DK. Effect of formulation factors on in vitro permeation of moxifloxacin from aqueous drops through excised goat, sheep, and buffalo corneas. AAPS PharmSciTech. 2006;7:E1–6.CrossRefGoogle Scholar
  25. 25.
    Srinivas N, Narasu L, Shankar BP, Mullangi R. Development and validation of a HPLC method for simultaneous quantitation of gatifloxacin, sparfloxacin and moxifloxacin using levofloxacin as internal standard in human plasma: application to a clinical pharmacokinetic study. Biomed Chromatogr. 2008;22:1288–95.CrossRefPubMedGoogle Scholar
  26. 26.
    Rodríguez IC, Cerezo A, Salem II. Sistemas de liberación bioadhesivos. ARs Pharm. 2000;1:115–28.Google Scholar
  27. 27.
    Ramkanth S, Chetty C. Design and evaluation of diclofenac sodium ocusert. PharmTech Res. 2009;1:1219–23.Google Scholar
  28. 28.
    Balaguer-Fernández C, Padula C, Femenía-Font A, Merino V, Santi P, López-Castellano A. Development and evaluation of occlusive systems employing polyvinyl alcohol for transdermal delivery of sumatriptan succinate. Drug Deliv. 2010;17:83–91.CrossRefPubMedGoogle Scholar
  29. 29.
    Femenía-Font A, Padula C, Marra F, Balaguer-Fernández C, Merino V, López-Castellano A, et al. Bioadhesive monolayer film for the in vitro transdermal delivery of sumatriptan. J Pharm Sci. 2006;95:1561–9.Google Scholar
  30. 30.
    Rathore MS, Majumdar DK. Effect of formulation factors on in vitro transcorneal permeation of gatifloxacin from aqueous drops. AAPS PharmSciTech. 2006;7:E1–6.CrossRefGoogle Scholar
  31. 31.
    Ubaidulla U, Reddy MVS, Ruckmani K, Ahmad FJ, Khar RK. Transdermal therapeutic system of carvedilol: effect of hydrophilic and hydrophobic matrix on in vitro and in vivo characteristics. AAPS PharmSciTech. 2007;8:2.CrossRefPubMedGoogle Scholar
  32. 32.
    Aqil M, Ali A, Sultana Y, Najmi AK. Fabrication and evaluation of polymeric films for transdermal delivery of pinacidil. Pharmazie. 2004;59:631–5.PubMedGoogle Scholar
  33. 33.
    Okamoto N, Ito Y, Nagai N, Murao T, Takiguchi Y, Kurimoto T, et al. Preparation of ophthalmic formulations containing cilostazol as an anti-glaucoma agent and improvement in its permeability through the rabbit cornea. J Oleo Sci. 2010;59:423–30.Google Scholar
  34. 34.
    Srirangam R, Majumdar S. Passive asymmetric transport of hesperetin across isolated rabbit cornea. Int J Pharm. 2010;394:60–7.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Chandran S, Roy A, Saha RN. Effect of pH and formulation variables on in vitro transcorneal permeability of flurbiprofen: a technical note. AAPS PharmSciTech. 2008;9:1031–7.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Van Der Bijl P, Engelbrecht AH, Van Eyk AD, Meyer D. Comparative permeability of human and rabbit corneas to cyclosporin and tritiated water. J Ocul Pharmacol Ther. 2002;18:419–27.CrossRefGoogle Scholar
  37. 37.
    Aburahma MH, Mahmoud AA. Biodegradable ocular inserts for sustained delivery of brimonidine tartarate: preparation and in vitro/in vivo evaluation. AAPS PharmSciTech. 2011;12:1335–47.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Franca JR, Foureaux G, Fuscaldi LL, et al. Bimatoprost-loaded ocular inserts as sustained release drug delivery systems for glaucoma treatment: in vitro and in vivo evaluation. PLoS One. 2014;9:e95461.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Jeganath S, Viji AA, Devi KS. Design and evaluation of controlled release ocuserts of indomethacin. Int J Pharm Sci Res. 2011;2:80–6.Google Scholar
  40. 40.
    Reddy DM, Reddy YK, Reddy DR, Kumar NV, Suresh M, Althaff M, et al. Formulation and evaluation of ciprofloxacin ocuserts. Res J Pharm Technol. 2011;4:1663–5.Google Scholar
  41. 41.
    Rao M, Nappinnai M, Raju S, Rao V, Reddy B. Fluconazole ocular inserts: formulation and in vitro evaluation. J Pharm Sci Res. 2010;2:344–50.Google Scholar
  42. 42.
    Kumari A, Sharma PK, Garg VK, Garg G. Ocular inserts—advancement in therapy of eye diseases. J Adv Pharm Technol Res. 2010;1:291–6.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Donnenfeld ED, Comstock TL, Proksch JW. Human aqueous humor concentrations of besifloxacin, moxifloxacin, and gatifloxacin after topical ocular application. J Cataract Refract Surg. 2011;37:1082–9.CrossRefPubMedGoogle Scholar

Copyright information

© Controlled Release Society 2017

Authors and Affiliations

  • María Sebastián-Morelló
    • 1
  • María Aracely Calatayud-Pascual
    • 1
  • Vicent Rodilla
    • 1
  • Cristina Balaguer-Fernández
    • 1
  • Alicia López-Castellano
    • 1
    Email author
  1. 1.Instituto de Ciencias Biomédicas, Departamento de Farmacia, Facultad de Ciencias de la SaludUniversidad Cardenal Herrera-CEU, CEU UniversitiesAlfara del PatriarcaSpain

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