Pharmaceutical Research

, Volume 26, Issue 3, pp 714–726 | Cite as

Controlled Release of High Molecular Weight Hyaluronic Acid from Molecularly Imprinted Hydrogel Contact Lenses

Research Paper

Abstract

Purpose

Current dry eye treatment includes delivering comfort agents to the eye via drops, but low bioavailability and multiple administration continues to be a barrier to effective treatment. There exists a significant unmet need for devices to treat dry eye and for more comfortable contact lenses.

Methods

Using molecular imprinting strategies with an analysis of biology, we have rationally designed and synthesized hydrogel contact lenses that can release hyaluronic acid (HA) at a controlled rate.

Results

Delayed release characteristics were significantly improved through biomimetic imprinting, as multiple functional monomers provided non-covalent complexation points within nelfilcon A gels without altering structural, mechanical, or optical properties. The diffusion coefficient of 1.2 million Dalton HA was controlled by varying the number and variety of functional monomers (increasing the variety lowered the HA diffusion coefficient 1.5 times more than single functional monomers, and 1.6 times more than nelfilcon A alone).

Conclusions

HA can be delivered from a daily disposable lens at a therapeutic rate of approximately 6 μg/h for 24 h. This is the first demonstration of imprinting a large molecular weight polymer within a hydrogel and the effect of imprinting on the reptation of the long chain macromolecule from the structure.

KEY WORDS

biomimetic comfort contact lenses controlled drug delivery dry eye molecular imprinted hydrogel therapeutic contact lenses 

Notes

Acknowledgements

We thank CIBA Vision, Inc. for funding this work and providing nefilcon macromers. We especially want to thank Dr. Lynn Winterton and Dr. John Pruitt for important discussions involving this work.

References

  1. 1.
    R. Berkow, M. H. Beers, R. M. Bogin, and A. J. Fletcher. The Merck Manual of Medical Information. Merck Research Laboratories, New Jersey, 1997.Google Scholar
  2. 2.
    J. P. Gilbard. Human tear film electrolyte concentrations in health and dry-eye disease. Int. Ophthalmol. Clin. 34:27–36 (1994). doi: 10.1097/00004397-199403410-00005.PubMedCrossRefGoogle Scholar
  3. 3.
    S. K. Gupta, V. Gupta, S. Joshi, and R. Tandon. Subclinically dry eyes in urban Delhi: an impact of air pollution? Ophthalmologica. 216:368–371 (2002). doi: 10.1159/000066183.PubMedCrossRefGoogle Scholar
  4. 4.
    C. A. Paschides, M. Stefaniotou, J. Papageorgiou, P. Skourtis, and K. Psilas. Ocular surface and environmental changes. Acta. Ophthalmol. Scand. 76:74–77 (1998). doi: 10.1034/j.1600-0420.1998.760113.x.PubMedCrossRefGoogle Scholar
  5. 5.
    P. Wolkoff, J. K. Nojgaard, C. Franck, and P. Skov. The modern office environment desiccates the eyes? Indoor Air. 16:258–265 (2006). doi: 10.1111/j.1600-0668.2006.00429.x.PubMedCrossRefGoogle Scholar
  6. 6.
    R. I. Fox. Sjogren's syndrome. Lancet. 366:321–331 (2005). doi: 10.1016/S0140-6736(05)66990-5.PubMedCrossRefGoogle Scholar
  7. 7.
    M. J. Glasson, F. Stapleton, L. Keay, and M. D. P. Willcox. The effect of short term contact lens wear on the tear film and ocular surface characteristics of tolerant and intolerant wearers. Contact Lens & Anterior Eye. 29:41–47 (2006). doi: 10.1016/j.clae.2005.12.006.CrossRefGoogle Scholar
  8. 8.
    Y. Hori, P. Argueso, S. Spurr-Michaud, and I. K. Gipson. Mucins and contact lens wear. Cornea. 25:176–181 (2006). doi: 10.1097/01.ico.0000177838.38873.2f.PubMedCrossRefGoogle Scholar
  9. 9.
    R. L. Chalmers, and C. G. Begley. Dryness symptoms among an unselected clinical population with and without contact lens wear. Contact Lens & Anterior Eye. 29:25–30 (2006). doi: 10.1016/j.clae.2005.12.004.CrossRefGoogle Scholar
  10. 10.
    P. Reddy, O. Grad, and K. Rajagopalan. The Economic Burden of Dry Eye. Cornea. 23:751–761 (2004). doi: 10.1097/01.ico.0000134183.47687.75.PubMedCrossRefGoogle Scholar
  11. 11.
    G. Young, J. Veys, N. Pritchard, and S. Coleman. A multi-centre study of lapsed contact lens wearers. Ophthalmic Physiol. Opt. 22:516–527 (2002). doi: 10.1046/j.1475-1313.2002.00066.x.PubMedCrossRefGoogle Scholar
  12. 12.
    J. C. Stuart, and J. G. Linn. Dilute sodium hyaluronate (Healon) in the treatment of ocular surface disorders. Ann Ophthalmol. 17:190–192 (1985).PubMedGoogle Scholar
  13. 13.
    P. Aragona, V. Papa, A. Micali, M. Santocono, and G. Milazzo. Long term treatment with sodium hyaluronate-containing artificial tears reduces ocular surface damage in patients with dry eye. Br. J. Ophthalmol. 86:181–184 (2002). doi: 10.1136/bjo.86.2.181.PubMedCrossRefGoogle Scholar
  14. 14.
    P. Aragona, G. Di Stefano, F. Ferreri, R. Spinella, and A. Stilo. Sodium hyaluronate eye drops of different osmolarity for the treatment of dry eye in Sjögren's syndrome patients. Br. J. Ophthalmol. 86:879–884 (2002). doi: 10.1136/bjo.86.8.879.PubMedCrossRefGoogle Scholar
  15. 15.
    F. Brignole, P. J. Pisella, B. Dupas, V. Baeyens, and C. Baudouin. Efficacy and safety of 0.18% sodium hyaluronate in patients with moderate dry eye syndrome and superficial keratitis. Graefe's Arch. Clin. Exp. Ophthalmol. 243:531–538 (2005). doi: 10.1007/s00417-004-1040-6.CrossRefGoogle Scholar
  16. 16.
    T. Hamano, K. Horimoto, M. Lee, and S. Komemushi. Sodium hyaluronate eyedrops enhance tear film stability. Jpn. J. Ophthalmol. 40:62–65 (1996).PubMedGoogle Scholar
  17. 17.
    K. Tsubota, and M. Yamada. Tear evaporation from the ocular surface. Invest. Ophthalmol. Vis. Sci. 33:2942–2950 (1992).PubMedGoogle Scholar
  18. 18.
    N. Nakamura, M. Hikida, T. Nakano, S. Ito, T. Hamano, and S. Kinoshita. Characterization of water retentive properties of hyaluronan. Cornea. 12:433–436 (1993). doi: 10.1097/00003226-199309000-00010.PubMedCrossRefGoogle Scholar
  19. 19.
    G. Camillieri, C. Bucolo, S. Rossi, and F. Drago. Hyaluronan-induced stimulation of corneal wound healing is a pure pharmacological effect. J. Ocul. Pharmacol. Ther. 20:548–553 (2004). doi: 10.1089/jop.2004.20.548.PubMedCrossRefGoogle Scholar
  20. 20.
    J. A. P. Gomes, R. Amankwah, A. Powell-Richards, and H. S. Dua. Sodium hyaluronate (hyaluronic acid) promotes migration of human corneal epithelial cells in vitro. Br. J. Ophthalmol. 88:821–825 (2004). doi: 10.1136/bjo.2003.027573.PubMedCrossRefGoogle Scholar
  21. 21.
    J. U. Prause. Treatment of keratoconjunctivitis sicca with Lacrisert. Scand J. Rheumatol Supple. 61:261–263 (1986).Google Scholar
  22. 22.
    C. Delattre, P. Michaud, J. Courtois, and M. A. Vijayalakshmi. Study of specific interactions between glucuronic acid and amino acids at the interface using pseudo bioaffinity chromatography and NMR studies. Curr. Sci. 94:1279–1284 (2008).Google Scholar
  23. 23.
    J. S. Park, Y. B. Lim, Y. M. Kwon, B. Jeong, Y. H. Choi, and S. W. Kim. Liposome fusion induced by pH-sensitive copolymer: Poly(4-vinylpyridine-co-N,N-diethylaminoethyl methacrylate). J. Polym. Sci. Part A: Polym. Chem. 37:2305–2309 (2000). doi: 10.1002/(SICI)1099-0518(19990715)37:14<2305::AID-POLA3>3.0.CO;2-5.CrossRefGoogle Scholar
  24. 24.
    J. Bajorath, B. Greenfield, S. B. Munro, A. J. Day, and A. Aruffo. Identification of CD44 residues important for hyaluronan binding and delineation of the binding site. J. Biol. Chem. 273:338–343 (1998). doi: 10.1074/jbc.273.1.338.PubMedCrossRefGoogle Scholar
  25. 25.
    S. Willis, J. L. Court, R. P. Redman, J. Wang, S. W. Leppard, V. J. O’Byrne, S. A. Small, A. L. Lewis, S. A. Jones, and P. W. Stratford. A novel phosphorylcholine-coated contact lens for extended wear use. Biomaterials. 22:3261–3272 (2001). doi: 10.1016/S0142-9612(01)00164-8.CrossRefGoogle Scholar
  26. 26.
    L. C. Winterton, J. M. Lally, K. B. Sentell, and L. L. Chapoy. The elution of poly (vinyl alcohol) from a contact lens: The realization of a time release moisturizing agent/artificial tear. J. Biomed. Mater Res. B: Appl. Biomater. 80B:424–432 (2006). doi: 10.1002/jbm.b.30613.Google Scholar
  27. 27.
    J. Nichols. Contact Lens Materials: A Look at Lubricating Agents in Daily Disposables. Contact Lens Spectrum, January (2007).Google Scholar
  28. 28.
    M. Van Beek, L. Jones, and H. Sheardown. Immobilized hyaluronic acid containing model silicone hydrogels reduce protein adsorption. J. Biomater. Sci., Polym. Ed. 12:1425–1436 (2008). doi: 10.1163/156856208786140364.CrossRefGoogle Scholar
  29. 29.
    M. Van Beek, A. Weeks, L. Jones, and H. Sheardown. Hyaluronic acid containing hydrogels for the reduction of protein adsorption. Biomaterials. 29:780–789 (2008). doi: 10.1016/j.biomaterials.2007.10.039.PubMedCrossRefGoogle Scholar
  30. 30.
    M. Ali. Therapeutic Contact Lenses for Comfort Molecules. Master's Thesis, Auburn University, December 2007.Google Scholar
  31. 31.
    M. E. Byrne, and V. Salian. Molecular Imprinting Within Hydrogels II: Progress and Analysis of the Field. Int. J. Pharm. 364:188–212 (2008). doi: 10.1016/j.ijpharm.2008.09.002.PubMedCrossRefGoogle Scholar
  32. 32.
    M. E. Byrne, K. Park, and N. A. Peppas. Molecular imprinting within hydrogels. Adv. Drug Del. Rev. 54:149–161 (2002). doi: 10.1016/S0169-409X(01)00246-0.CrossRefGoogle Scholar
  33. 33.
    J. Z. Hilt, and M. E. Byrne. Configurational biomimesis in drug delivery: molecular imprinting of biologically significant molecules. Adv. Drug Del. Rev. 56:1599–1620 (2004). doi: 10.1016/j.addr.2004.04.002.CrossRefGoogle Scholar
  34. 34.
    B. Sellergren, and C. J. Allender. Molecularly imprinted polymers: A bridge to advanced drug delivery. Adv. Drug Del. Rev. 57:1733–1741 (2005). doi: 10.1016/j.addr.2005.07.010.CrossRefGoogle Scholar
  35. 35.
    D. Cunliffe, A. Kirby, and C. Alexander. Molecularly imprinted drug delivery systems. Adv. Drug Del. Rev. 57:1836–1853 (2005).Google Scholar
  36. 36.
    C. Alvarez-Lorenzo, and A. Concheiro. Molecularly imprinted polymers for drug delivery. J. Chromatogr. B. 804:231–245 (2004). doi: 10.1016/j.jchromb.2003.12.032.CrossRefGoogle Scholar
  37. 37.
    C. J. Allender, C. Richardson, B. Woodhouse, C. M. Heard, and K. R. Brain. Pharmaceutical applications for molecularly imprinted polymers. Int. J. Pharm. 195:39–43 (2000). doi: 10.1016/S0378-5173(99)00355-5.PubMedCrossRefGoogle Scholar
  38. 38.
    S. Venkatesh, S. P. Sizemore, and M. E. Byrne. Biomimetic hydrogels for enhanced loading and extended release of ocular therapeutics. Biomaterials. 28:717–724 (2007). doi: 10.1016/j.biomaterials.2006.09.007.PubMedCrossRefGoogle Scholar
  39. 39.
    S. Venkatesh, S. P. Sizemore, J. B. Zhang, and M. E. Byrne. Therapeutic contact lenses: a biomimetic approach towards tailored ophthalmic extended delivery. Polymeric Materials: Science & Engineering (PMSE) Preprints. 94:766–767 (2006).Google Scholar
  40. 40.
    C. Alvarez-Lorenzo, F. Yanez, R. Barreiro-Iglesias, and A. Concheiro. Imprinted soft contact lenses as norfloxacin delivery systems. J. Controlled Release. 113:236–244 (2006). doi: 10.1016/j.jconrel.2006.05.003.CrossRefGoogle Scholar
  41. 41.
    H. Hiratani, Y. Mizutani, and C. Alvarez-Lorenzo. Controlling drug release from imprinted hydrogels by modifying the characteristics of the imprinted cavities. Macromol. Biosci. 5:728–733 (2005). doi: 10.1002/mabi.200500065.PubMedCrossRefGoogle Scholar
  42. 42.
    S. Venkatesh, J. Saha, S. Pass, and M. E. Byrne. Transport and structural analysis of molecularly imprinted hydrogels for controlled drug delivery. Eur. J. Pharm. Biopharm. 69(3):852–860 (2008). doi: 10.1016/j.ejpb.2008.01.036.PubMedCrossRefGoogle Scholar
  43. 43.
    C. Alvarez-Lorenzo, H. Hiratani, and A. Concheiro. Contact Lenses for Drug Delivery. Am. J. Drug Del. 4:131–151 (2006). doi: 10.2165/00137696-200604030-00002.CrossRefGoogle Scholar
  44. 44.
    M. Ali, and M. E. Byrne. Challenges and solutions in topical ocular drug-delivery systems. Exp. Rev. Clin. Pharmacol. 1:145–161 (2008). doi: 10.1586/17512433.1.1.145.CrossRefGoogle Scholar
  45. 45.
    N. Bühler, H. P. Haerr, M. Hofmann, C. Irrgang, A. Mühlebach, B. Müller, and F. Stockinger. Nelfilcon A, a New Material for Contact Lenses. Chimia. 53:269–274 (1999).Google Scholar
  46. 46.
    L. Michaud, and C. J. Giasson. Overwear of contact lenses: increased severity of clinical signs as a function of protein adsorption. Optom. Vis. Sci. 79:184–192 (2002). doi: 10.1097/00006324-200203000-00013.PubMedCrossRefGoogle Scholar
  47. 47.
    N. J. Van Haeringen. Clinical Biochemistry of Tears. Surv. Ophthalmol. 26:84–96 (1981). doi: 10.1016/0039-6257(81)90145-4.PubMedCrossRefGoogle Scholar
  48. 48.
    J. Crank. The Mathematics of Diffusion. Oxford University Press, Oxford, 1975.Google Scholar
  49. 49.
    N. A. Peppas. Hydrogels in Medicine and Pharmacy, Volumes I & II. CRC, Boca Raton, 1987.Google Scholar
  50. 50.
    P. J. Flory. Principles of Polymer Chemistry. Cornell University Press, Ithaca, 1953.Google Scholar
  51. 51.
    P. J. Flory, and J. Rehner. Statistical mechanics of cross-linked polymer networks. I. Rubberlike elasticity. J. Chem. Phys. 11:512–520 (1943). doi: 10.1063/1.1723791.CrossRefGoogle Scholar
  52. 52.
    P. J. Flory, and J. Rehner. Statistical mechanics of cross-linked polymer networks. II. Swelling. J. Chem. Phys. 11:521–526 (1943). doi: 10.1063/1.1723792.CrossRefGoogle Scholar
  53. 53.
    Z. Sklubalova, and Z. Zatloukal. Systematic study of factors affecting eye drop size and dosing variability. Pharmazie. 60:917–921 (2005).PubMedGoogle Scholar
  54. 54.
    P. G. de Gennes. Reptation of a polymer chain in the presence of fixed obstacles. J. Chem. Phys. 55:572–279 (1971). doi: 10.1063/1.1675789.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Biomimetic & Biohybrid Materials, Biomedical Devices, and Drug Delivery Laboratories, Department of Chemical EngineeringAuburn UniversityAuburnUSA

Personalised recommendations