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Computer Simulation of Convective and Diffusive Transport of Controlled-Release Drugs in the Vitreous Humor

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Abstract

Purpose. Biodistribution of drugs in the eye is central to the efficacy of pharmaceutical ocular therapies. Of particular interest to us is the effect of intravitreal transport on distribution of controlled-released drugs within the vitreous.

Methods. A computer model was developed to describe the three-dimensional convective-diffusive transport of drug released from an intravitreal controlled release source. Unlike previous studies, this work includes flow of aqueous from the anterior to the posterior of the vitreous. The release profile was based on in vitro release of gentamicin from poly(L-lactic acid) microspheres into vitreous.

Results. For small drugs, convection plays a small role, but for large (slower diffusing) drugs, convection becomes more important. For the cases studied, the predicted ratio of drug reaching the retina to drug cleared by the aqueous humor was 2.4 for a small molecule but 13 for a large molecule. Transport in neonatal mouse eye, in contrast, was dominated by diffusion, and the ratio decreased to 0.39.

Conclusions. The interaction among convection, diffusion, and geometry causes significant differences in biodistribution between large and small molecules or across species. These differences should be considered in the design of delivery strategies or animal studies.

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REFERENCES

  1. W. M. Hart. Adler's Physiology of the Eye, Mosby-Year Book, Chicago, Illinois, 1992.

    Google Scholar 

  2. W. H. Stern, G. P. Lewis, P. A. Erickson, C. J. Guerin, D. H. Anderson, S. K. Fisher, and J. J. O'Donnell. Fluorouracil Therapy for Proliferative Vitreoretinopathy After Vitrectomy. Am. J. Ophthalmol. 96:33-42 (1983).

    Google Scholar 

  3. G. M. Bleeker. N. J. V. Haeringen, E. R. Mass, and E. Glasius. Selective Properties of the Vitreous Barrier. Exp. Eye Res. 7:37-46 (1968).

    Google Scholar 

  4. F. Q. Liang and R. S. Viola. M. d. Cerro, and V. Aquavella. Noncross-linked Collagen Discs and Cross-linked Collagen Shields in the Delivery of Gentamicin to Rabbits Eyes. Invest. Ophthalmol. Vis. Sci. 33:2194-2198 (1992).

    Google Scholar 

  5. G. G. Giordano, M. F. Refojo, and M. H. Arroyo. Sustained Delivery of Retinoic Acid from Microspheres of Biodegradable Polymer in PVR. Invest. Ophthalmol. Vis. Sci. 34:2743-2751 (1993).

    Google Scholar 

  6. H. Miyamoto, Y. Ogura, M. Hashizoe, N. Kunou, Y. Honda, and Y. Ikada. Biodegradable Scleral Implant for Intravitreal Controlled Release of Fluconazole. Curr. Eye Res. 16:930-935 (1997).

    Google Scholar 

  7. S. C. Pflugfelder, E. Hernandez, and S. J. Fliesler. and J. Alvarez. Intravitreal Vancomycin. Retinal Toxicity, Clearance, and Interaction with Gentamicin. Arch. Ophthalmol. 105:831-837 (1987).

    Google Scholar 

  8. R. T. Falk, T. W. Randolph, J. Meyer, R. Kelly, and M. Manning. Controlled Release of Ionic Compounds from Poly (L-lactide) Microspheres Produced by Precipitaion with a Compressed Antisolvent. J. Control. Release 44:77-85 (1997).

    Google Scholar 

  9. J. D. Meyer, R. F. Falk, R. M. Kelley, J. E. Shively, S. J. Withrow, W. S. Dernell, D. J. Kroll, T. W. Randolph, and M. C. Manning. Preparation and In Vitro Characterization of Gentamicin-Impregnated Biodegradable Beads Suitable for Treatment of Osteomyelitis. J. Pharm. Sci. 87:1149-1154 (1997).

    Google Scholar 

  10. W. Dernell, S. Withrow, M. Manning, C. Kuntz, R. Dewell, F. Garry, B. Powers, J. Shively, R. Falk, and T. Randolph. In Vivo Evaluation of Gentamicin-Impregnated Polylactic Acid Beads Implanted in Sheep. J. Bioact. and Compat. Polym. 16:119-135 (2001).

    Google Scholar 

  11. W. Dernell, C. Gentry-Weeks, M. Manning, B. Powers, R. Park, M. Lafferty, C. Kuntz, J. Shively, R. Falk, J. Meyer, T. Randolph, and S. Withrow. In Vivo Evaluation of Anibiotic Impregnated beads in a Rat Osteomyelitis Model. J. Bioact. Compat. Polym. 16:235-250 (2001).

    Google Scholar 

  12. J. Xu. Controlled release and the concentration distribution of the drug in the vitreous humor. M. S. Thesis in Chemical Engineering, University of Colorado, Boulder, Colorado, 1999.

    Google Scholar 

  13. J. Xu, J. J. Heys, T. W. Randolph, and V. H. Barocas. Permeability, and diffusion in the vitreous humor: Implications for controlled drug delivery. Pharm. Res. 17:664-669 (2000).

    Google Scholar 

  14. A. Ohtori and K. J. Toko. In Vivo/In Vitro Correlation of Intravitreal Delivery of Drugs With the Help of Computer Simulation. Biol. Pharm. Bull. 17:283-290 (1994).

    Google Scholar 

  15. M. Araie and D. Maurice. The Loss of Flourescein, Flourescein Glucuronide and Flourescein Isothiocyanate Dextran from the Vitreous by the Anterior and Retinal Pathways. Exp. Eye Res. 52:27-39 (1991).

    Google Scholar 

  16. S. Friedrich, Y. Cheng, and B. Saville. Drug Distribution in the Vitreous Humor of the Human Eye: The Effect of Intravitreal Injection Position and Volume. Curr. Eye Res. 16:663-669 (1997).

    Google Scholar 

  17. I. Fatt and B. Hedbys. Flow of water in the sclera. Exp. Eye Res. 10:243-249 (1970).

    Google Scholar 

  18. W. G. Robison, T. Kuwabara, and J. Zwaan. Eye research. In H. L. Foster, J. D. Small, and J. G. Fox (eds.), The Mouse in Biomedical Research. Volume IV. Experimental Biology and Oncology, Academic Press, New York, 1982 pp. 69-89.

    Google Scholar 

  19. P. A. Pearson, G. J. Jaffe, D. F. Martin, G. J. Cordahi, H. Grossniklaus, E. T. Schmeisser, and P. Ashton. Evaluation of a delivery system providing long-term release of cyclosporine. Arch. Ophthalmol. 114:311-317 (1996).

    Google Scholar 

  20. C. B. Engler, B. Sander, M. Larsen, P. Dalgaard, and H. Lund-Andersen. Fluorescein Transport Across the Human Blood Retina Barrier in the Direction Vitreous to Blood-Quantitative Assessment in-Vivo. Acta Ophthalmol. (Copenh.) 72:655-662 (1994).

    Google Scholar 

  21. B. Moldow, B. Sander, M. Larsen, and H. Lund-Andersen. Effects of acetazolamide on passive and active transport of fluorescein across normal BRB. Invest. Ophthalmol. Vis. Sci. 40:1771-1775 (1999).

    Google Scholar 

  22. D. Maurice. Flow of water between aqueous and vitreous compartments in the rabbit eye. Am. J. Physiol. 252:F104-F108 (1987).

    Google Scholar 

  23. S. Tsuboi and J. E. Pederson. Effect of plasma osmolality and intraocular pressure on fluid movement across the blood-retinal barrier. Invest. Ophthalmol. Vis. Sci. 29:1747-1749 (1988).

    Google Scholar 

  24. M. Johnson and K. Erickson. Mechanisms and routes of aqueous humor drainage. In D. M. Albert and F. A. Jakobiec (eds.), Glaucoma, W.B. Saunders: Philadelphia, Pennsylvania, 2000 pp. 2577-2594.

    Google Scholar 

  25. Y. Sugiura and M. Araie. Effects of intraocular pressure change on movement of FITC-dextran across vitreous-aqueous interface. Jpn. J. Ophthalmol. 33:441-450 (1989).

    Google Scholar 

  26. H. M. Cheng, K. K. Kwong, J. Xiong, and B. T. Woods. Visualization of water movement in the living rabbit eye. Graefes Arch. Clin. Exp. Ophthalmol. 230:62-65 (1992).

    Google Scholar 

  27. S. Koyano, M. Araie, and S. Eguchi. Movement of fluorescein and its glucuronide across retinal pigment epithelium-choroid. Invest. Ophthalmol. Vis. Sci. 34:531-538 (1993).

    Google Scholar 

  28. A. Yoshida, M. Kojima, and S. Ishiko. Inward and outward permeability of the blood-retinal barrier. In J. Cunha-Vaz and E. Leite (eds.). Ocular Fluorophotometry and the Future, Kugler & Ghedini Publishers, Amsterdam, 1989, pp. 89-97.

    Google Scholar 

  29. A. Yoshida, S. Ishiko, and M. Kojima. Outward Permeability of Blood-Retinal Barrier. Graefes Arch. Clin. Exp. Ophthalmol. 230:78-83 (1992).

    Google Scholar 

  30. S. Friedrich, B. Saville, and Y. Cheng. Finite Element Modeling of Drug Distribution in the Vitreous Humor of the Rabbit Eye. Annals Biomed. Eng. 25:303-314 (1997).

    Google Scholar 

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Authors and Affiliations

  1. Graduate Program in Scientific Computation, University of Minnesota, Minneapolis, Minnesota, 55455

    Matthew S. Stay & Victor H. Barocas

  2. Department of Chemical Engineering, University of Colorado, Boulder, Colorado, 80309-0424

    Jing Xu & Theodore W. Randolph

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  1. Matthew S. Stay
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  2. Jing Xu
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  3. Theodore W. Randolph
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  4. Victor H. Barocas
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Correspondence to Victor H. Barocas.

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Stay, M.S., Xu, J., Randolph, T.W. et al. Computer Simulation of Convective and Diffusive Transport of Controlled-Release Drugs in the Vitreous Humor. Pharm Res 20, 96–102 (2003). https://doi.org/10.1023/A:1022207026982

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