AAPS PharmSciTech

, 10:796 | Cite as

Development of an Ex Vivo Method for Evaluation of Precorneal Residence of Topical Ophthalmic Formulations

Research Article

Abstract

This paper describes the development of an ex vivo perfusion method for the evaluation of topical ophthalmic formulations. The perfusion system developed consisted of a perfusion chamber, two precision pumps to control the in/out flow rates to simulate the tear flow rate, and a fluorescence microscope imager. Freshly excised rat cornea was used as a biomembrane. Fluorescein (FITC) was used as a marker. Residence time was determined by measuring fluorescence intensity over time after application of the formulation to the cornea. In addition, viscoelastic properties of the formulations were measured and correlated to the retention times. The perfusion method easily differentiated formulations based on the retention time on the cornea: For example, a 0.3% hydroxypropyl methylcellulose formulation had a short retention time of <10 min. Addition of 0.25% carboxymethylcellulose increased the retention time from less than 10 min to over 16 min, and addition of 0.1% Carbopol further increased retention time to over 40 min. For alginate formulations, the retention time was significantly longer in the presence of 0.06% calcium chloride than that of 0.006% calcium chloride. The longer residence time at a higher Ca++ concentration can be attributed to the greater elastic modulus associated with the gel. Interestingly, however, a hyaluronate formulation displayed a very long retention time but has low viscoelastic moduli. This suggests that the mucoadhesive properties may not always be discernable by the rheological properties. The ex vivo perfusion method may in fact provide more meaningful information with regard to retention times of formulations.

Key words

ex vivo ophthalmic formulation perfusion residence retention 

Notes

Acknowledgment

The authors wish to thank Paul Grosenstein for providing rat cornea used in this study.

References

  1. 1.
    Maurice DM. Kinetics of topical applied drugs. In: Saettone MS, Bucci P, Speiser P, editors. Ophthalmic drug delivery, biopharmaceutical, technological and clinical aspects. Padova: Liviana; 1987. p. 19–26.Google Scholar
  2. 2.
    Bourlias CL, Acar L, Zia H, Soda PA, Needham T, Leverge R. Ophthalmic drug delivery systems-recent advances. Prog Retinal Eye Res. 1998;17:33–58.CrossRefGoogle Scholar
  3. 3.
    Ding S. Recent development in ophthalmic drug delivery. Pharm Sci Technol Today. 1998;1:328–35.CrossRefGoogle Scholar
  4. 4.
    Lee Y, Millard J, Negvesky G, Butrus S, Yalkowsky S. Formulation and in vivo evaluation of ocular insert containing phenylephrine and tropicamide. Int J Pharm. 1999;182:121–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Hill JM, O’Callaghan RJ, Hobden JA, Kaufman E. Controlled collagen shields for ocular delivery. In: Mitra AK, editor. Ophthalmic drug delivery systems. New York: Marcel Dekker; 1993. p. 261–275.Google Scholar
  6. 6.
    El-kamel A. In vitro and in vivo evaluation of Pluronic F127-based ocular delivery system for timolol maleate. Int J Pharm. 2002;241:47–55.PubMedCrossRefGoogle Scholar
  7. 7.
    Liu Z, Li J, Nie S, Liu H, Ding P, Pan W. Study of an alginate/HPMC-based in situ gelling ophthalmic delivery system for gatifloxacin. Int J Pharm. 2006;315:12–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Carlfors J, Edsman K, Petersson R, Jornving K. Rheological evaluation of Gelrite in situ gels for ophthalmic use. Eur J Pharm Sci. 1998;6:113–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Nagarsenker M, Londhe V, Nadkarni G. Preparation and evaluation of liposomal formulations of tropicamide for ocular delivery. Int J Pharm. 1999;190:63–71.PubMedCrossRefGoogle Scholar
  10. 10.
    El-Gazeyerly O, Hikal A. Preparation and evaluation of acetazolamide liposome as an ocular delivery system. Int J Pharm. 1997;158:121–7.CrossRefGoogle Scholar
  11. 11.
    Bochot A, Fattal E, Grossiord J, Puisieux F, Couvreur P. Characterization of a new ocular delivery system based on a dispersion of liposomes in a thermosensitive gel. Int J Pharm. 1998;162:119–27.CrossRefGoogle Scholar
  12. 12.
    Zimmer A, Zerbe H, Kreuter J. Evaluation of pilocarpine-loaded albumin particles as drug delivery system for controlled delivery in the eye I. in vitro and in vivo characterization. J Control Release. 1994;32:57–70.CrossRefGoogle Scholar
  13. 13.
    Chiang C, Tung S, Lu D, Yeh M. In vitro and in vivo evaluation of an ocular delivery system of 5-fluorouracil microsphere. J Ocul Pharmacol Ther. 2001;17:545–53.PubMedCrossRefGoogle Scholar
  14. 14.
    Madsen F, Eberth K, Smart J. A rheological examination of the mucoadhesive/mucus interaction: the effect of mucoadhesive type and concentration. J Control Release. 1998;50:167–78.PubMedCrossRefGoogle Scholar
  15. 15.
    Ceulelmans J, Ludwig A. Optimization of carbomer viscous eye drops: an in vitro experimental design approach using rheological techniques. Eur J Pharm Biopharm. 2002;54:41–50.CrossRefGoogle Scholar
  16. 16.
    Hagerstrom H, Paulsson M, Edsman K. Evaluation of mucoadhesion for two polyelectrolyte gels in stimulated physiological conditions using a rheological method. Eur J Pharm Sci. 2000;9:301–09.PubMedCrossRefGoogle Scholar
  17. 17.
    Ceulemans J, Vinckier I, Ludwig A. The use of xanthan gum in an ophthalmic liquid dosage form: rheological characterization of the interaction with mucin. J Pharm Sci. 2002;91:1117–27.PubMedCrossRefGoogle Scholar
  18. 18.
    Barbault-Foucher S, Gref R, Russo P, Gunechot J, Bochot A. Design of ploy-ε-caprolactone nanospheres coated with bioadhesive hyaluronic acid for ocular delivery. J Control Release. 2002;83:365–75.PubMedCrossRefGoogle Scholar
  19. 19.
    Tei M, Moccia R, Gipson IK. Developmental expression of mucin genes ASGP (rMuc4) and rMuc5ac by the rat ocular surface epithelium. Invest Opthalmo Vis Sci. 1999;40:1944–51.Google Scholar
  20. 20.
    Nagyova B, Tiffany JM. Components responsible for the surface tension of human tears. Curr Eye Res. 1999;19:4–11.PubMedCrossRefGoogle Scholar
  21. 21.
    Argueso P, Gipson IK. Epithelial mucins of the ocular surface: structure, biosynthesis and function. Exp Eye Res. 2001;73:281–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Jannari E, Peppas NA. Polymer–polymer interfusion and adhesion. JMS Rev Macromol Chem Phys. 1994;C34:205–41.Google Scholar
  23. 23.
    Robert C, Buri P, Peppas NA. Experimental method for bioadhesive testing of various polymers. Acta Pharm Technol. 1988;34:95–8.Google Scholar
  24. 24.
    Shah A, Donovan M. Formulating gels for decreased mucociliary transport using rheologic properties: polyacrylic acids. AAPS PharmSciTech. 2007;8(2):Article 33.PubMedGoogle Scholar
  25. 25.
    Edsman K, Carlfors J, Harju K. Rheological evaluation and ocular contact time of some carbomer gels for ophthalmic use. Int J Pharm. 1996;137:233–41.CrossRefGoogle Scholar
  26. 26.
    Tamburic S, Craig D. A comparison of different in vitro methods for measuring mucoadhesive performance. Eur J Pharm Biopharm. 1997;44:159–67.CrossRefGoogle Scholar
  27. 27.
    Mortazavi SA, Carpenter BG, Smart JD. A comparative study on the role played by mucus glycoproteins in the rheological behavior of the mucoadhesive/mucosal interface. In J Pharm. 1993;83:221–5.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2009

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, School of PharmacyTemple UniversityPhiladelphiaUSA
  2. 2.DEV-PDU-3Novartis Pharmaceuticals CorporationEast HanoverUSA

Personalised recommendations