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Gelling hypotonic polymer solution for extended topical drug delivery to the eye

Nature Biomedical Engineering volume 4, pages 1053–1062 (2020)Cite this article

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Abstract

Eye-drop formulations should hold as high a concentration of soluble drug in contact with ocular epithelium for as long as possible. However, eye tears and frequent blinking limit drug retention on the ocular surface, and gelling drops typically form clumps that blur vision. Here, we describe a gelling hypotonic solution containing a low concentration of a thermosensitive triblock copolymer for extended ocular drug delivery. On topical application, the hypotonic formulation forms a highly uniform and clear thin layer that conforms to the ocular surface and resists clearance from blinking, increasing the intraocular absorption of hydrophilic and hydrophobic drugs and extending the drug–ocular-epithelium contact time with respect to conventional thermosensitive gelling formulations and commercial eye drops. We also show that the conformal gel layer allows for therapeutically relevant drug delivery to the posterior segment of the eyeball in pigs. Our findings highlight the importance of formulations that conform to the ocular surface before viscosity enhancement for increased and prolonged ocular surface contact and drug absorption.

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Fig. 1: Hypotonicity drives water absorption that leads to uniform ocular surface coating and gelation.
Fig. 2: Hypotonic gelling formulation (12% hypo) provides increased intraocular absorption of water-soluble BT (0.15% w/v) compared with the conventional gelling formulation (18% iso) or the commercially available formulation (Alphagan P).
Fig. 3: Hypotonic gelling formulation (12% hypo) solubilizes and provides improved intraocular delivery of two insoluble drugs, BRZ (1% w/v) and CsA (0.05% w/v), compared with the conventional gelling formulation (18% iso) or the commercially available formulations (Azopt and Restasis).
Fig. 4: Once-daily dosing of the hypotonic gelling formulation (12% hypo) containing water-soluble ACF (0.5% w/v) and SM (0.4% w/v) in mice suppresses laser-induced CNV.
Fig. 5: Hypotonic gelling formulation (12% hypo) provides therapeutically relevant delivery of SM (0.4% w/v) to the posterior segment with once-daily dosing in rabbits and pigs.
Fig. 6: Hypotonic gelling formulation (12% hypo) is indistinguishable from untreated with twice-daily dosing for 5 weeks in rabbits.

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Data availability

The main data supporting the findings of this study are available within the paper and its Supplementary information. The associated raw data are too large to be readily shared publicly but are available from the corresponding author on reasonable request.

References

  1. Urtti, A., Pipkin, J. D., Rork, G. & Repta, A. J. Controlled drug delivery devices for experimental ocular studies with timolol 1. In vitro release studies. Int. J. Pharm. 61, 235–240 (1990).

    CAS  Google Scholar 

  2. Hermann, M. M., Papaconstantinou, D., Muether, P. S., Georgopoulos, G. & Diestelhorst, M. Adherence with brimonidine in patients with glaucoma aware and not aware of electronic monitoring. Acta Ophthalmol. 89, E300–E305 (2011).

    Google Scholar 

  3. Agrawal, A. K., Das, M. & Jain, S. In situ gel systems as ‘smart’ carriers for sustained ocular drug delivery. Expert Opin. Drug Del. 9, 383–402 (2012).

    CAS  Google Scholar 

  4. Dumortier, G., Grossiord, J. L., Agnely, F. & Chaumeil, J. C. A review of poloxamer 407 pharmaceutical and pharmacological characteristics. Pharm. Res. 23, 2709–2728 (2006).

    CAS  Google Scholar 

  5. Rowe, R. C., Sheskey, P. J., Owen, S. C. & American Pharmacists Association. Handbook of Pharmaceutical Excipients 6th edn (Pharmaceutical Press, 2009).

  6. Escobar-Chavez, J. J. et al. Applications of thermo-reversible pluronic F-127 gels in pharmaceutical formulations. J. Pharm. Pharm. Sci. 9, 339–358 (2006).

    CAS  Google Scholar 

  7. Schuster, B. S., Ensign, L. M., Allan, D. B., Suk, J. S. & Hanes, J. Particle tracking in drug and gene delivery research: state-of-the-art applications and methods. Adv. Drug Deliv. Rev. 91, 70–91 (2015).

    CAS  Google Scholar 

  8. Squires, T. M. & Mason, T. G. Fluid mechanics of microrheology. Annu. Rev. Fluid Mech. 42, 413–438 (2010).

    Google Scholar 

  9. Ensign, L. M., Schneider, C., Suk, J. S., Cone, R. & Hanes, J. Mucus penetrating nanoparticles: biophysical tool and method of drug and gene delivery. Adv. Mater. 24, 3887–3894 (2012).

    CAS  Google Scholar 

  10. Zignani, M., Tabatabay, C. & Gurny, R. Topical semi-solid drug delivery: kinetics and tolerance of ophthalmic hydrogels. Adv. Drug Deliv. Rev. 16, 51–60 (1995).

    CAS  Google Scholar 

  11. Cantor, L. B. Brimonidine in the treatment of glaucoma and ocular hypertension. Ther. Clin. Risk Manag. 2, 337–346 (2006).

    CAS  Google Scholar 

  12. McDougal, A. J. (ed.) Pharmacology/Toxicology NDA Review And Evaluation Simbrinza (NDA204251) (Food and Drug Administration Center for Drug Evaluation and Research, 2012).

  13. Hackett, S. F. et al. Sustained delivery of acriflavine from the suprachoroidal space provides long term suppression of choroidal neovascularization. Biomaterials 243, 119935 (2020).

    CAS  Google Scholar 

  14. Tsujinaka, H. et al. Sustained treatment of retinal vascular diseases with self-aggregating sunitinib microparticles. Nat. Commun. 11, 694 (2020).

    CAS  Google Scholar 

  15. Fathalla, Z. M. A. et al. Poloxamer-based thermoresponsive ketorolac tromethamine in situ gel preparations: design, characterisation, toxicity and transcorneal permeation studies. Eur. J. Pharm. Biopharm. 114, 119–134 (2017).

    CAS  Google Scholar 

  16. Abdelkader, H., Ismail, S., Kamal, A. & Alany, R. G. Design and evaluation of controlled-release niosomes and discomes for naltrexone hydrochloride ocular delivery. J. Pharm. Sci. 100, 1833–1846 (2011).

    CAS  Google Scholar 

  17. Rodrigues, G. A. et al. Topical drug delivery to the posterior segment of the eye: addressing the challenge of preclinical to clinical translation. Pharm. Res. 35, 245 (2018).

    Google Scholar 

  18. Goodman, V. L. et al. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin. Cancer Res. 13, 1367–1373 (2007).

    CAS  Google Scholar 

  19. Roskoski, R. Jr. Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochem. Biophys. Res. Commun. 356, 323–328 (2007).

    CAS  Google Scholar 

  20. Craig, J. P., Simmons, P. A., Patel, S. & Tomlinson, A. Refractive index and osmolality of human tears. Optom. Vis. Sci. 72, 718–724 (1995).

    CAS  Google Scholar 

  21. Gonzalez-Meijome, J. M. et al. Refractive index and equilibrium water content of conventional and silicone hydrogel contact lenses. Ophthalmic Physiol. Opt. 26, 57–64 (2006).

    Google Scholar 

  22. Patel, A., Cholkar, K., Agrahari, V. & Mitra, A. K. Ocular drug delivery systems: an overview. World J. Pharm. 2, 47–64 (2013).

    CAS  Google Scholar 

  23. Deokule, S., Sadiq, S. & Shah, S. Chronic open angle glaucoma: patient awareness of the nature of the disease, topical medication, compliance and the prevalence of systemic symptoms. Ophthal. Physiol. Opt. 24, 9–15 (2004).

    Google Scholar 

  24. Inoue, K. Managing adverse effects of glaucoma medications. Clin. Ophthalmol. 8, 903–913 (2014).

    CAS  Google Scholar 

  25. Schwartz, G. F. & Quigley, H. A. Adherence and persistence with glaucoma therapy. Surv. Ophthalmol. 53 (Suppl. 1), S57–S68 (2008).

    Google Scholar 

  26. Stewart, W. C., Chorak, R. P., Hunt, H. H. & Sethuraman, G. Factors associated with visual loss in patients with advanced glaucomatous changes in the optic nerve head. Am. J. Ophthalmol. 116, 176–181 (1993).

    CAS  Google Scholar 

  27. Shedden, A., Laurence, J., Tipping, R. & Timoptic, X. E. S. G. Efficacy and tolerability of timolol maleate ophthalmic gel-forming solution versus timolol ophthalmic solution in adults with open-angle glaucoma or ocular hypertension: a six-month, double-masked, multicenter study. Clin. Ther. 23, 440–450 (2001).

    CAS  Google Scholar 

  28. Walters, T. R. et al. Efficacy and tolerability of 0.5% timolol maleate ophthalmic gel-forming solution QD compared with 0.5% levobunolol hydrochloride BID in patients with open-angle glaucoma or ocular hypertension. Clin. Therapeutics 20, 1170–1178 (1998).

    CAS  Google Scholar 

  29. Lira, M., Pereira, C., Real Oliveira, M. E. & Castanheira, E. M. Importance of contact lens power and thickness in oxygen transmissibility. Cont. Lens Anterior Eye 38, 120–126 (2015).

    Google Scholar 

  30. Olsen, T. On the calculation of power from curvature of the cornea. Br. J. Ophthalmol. 70, 152–154 (1986).

    CAS  Google Scholar 

  31. Jager, R. D., Aiello, L. P., Patel, S. C. & Cunningham, E. T. Risks of intravitreous injection: a comprehensive review. Retina 24, 676–698 (2004).

    Google Scholar 

  32. Singer, M. A. et al. HORIZON: an open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology 119, 1175–1183 (2012).

    Google Scholar 

  33. Friedrich, S., Cheng, Y. L. & Saville, B. Drug distribution in the vitreous humor of the human eye: the effects of intravitreal injection position and volume. Curr. Eye Res. 16, 663–669 (1997).

    CAS  Google Scholar 

  34. Kaplan, H. J., Chiang, C. W., Chen, J. & Song, S. K. Vitreous volume of the mouse measured by quantitative high-resolution MRI. Invest. Ophthalmol. Vis. Sci. 51, 4414 (2010).

    Google Scholar 

  35. Doughty, M. J. & Zaman, M. L. Human corneal thickness and its impact on intraocular pressure measures: a review and meta-analysis approach. Surv. Ophthalmol. 44, 367–408 (2000).

    CAS  Google Scholar 

  36. Zhang, H. et al. The measurement of corneal thickness from center to limbus in vivo in C57BL/6 and BALB/c mice using two-photon imaging. Exp. Eye Res. 115, 255–262 (2013).

    CAS  Google Scholar 

  37. Park, H. et al. Assessment of axial length measurements in mouse eyes. Optom. Vis. Sci. 89, 296–303 (2012).

    Google Scholar 

  38. Bekerman, I., Gottlieb, P. & Vaiman, M. Variations in eyeball diameters of the healthy adults. J. Ophthalmol. 2014, 503645 (2014).

    Google Scholar 

  39. Iwase, T. et al. Topical pazopanib blocks VEGF-induced vascular leakage and neovascularization in the mouse retina but is ineffective in the rabbit. Invest. Ophthalmol. Vis. Sci. 54, 503–511 (2013).

    CAS  Google Scholar 

  40. Boettger, M. K., Klar, J., Richter, A. & von Degenfeld, G. Topically administered regorafenib eye drops inhibit grade IV lesions in the non-human primate laser CNV model. Invest. Ophthalmol. Vis. Sci. 56, 2294 (2015).

    Google Scholar 

  41. Joussen, A. M. et al. The developing regorafenib eye drops for neovascular age-related macular degeneration (DREAM) study: an open-label phase II trial. Brit J. Clin. Pharm. 85, 347–355 (2019).

    CAS  Google Scholar 

  42. Horita, S. et al. Species differences in ocular pharmacokinetics and pharmacological activities of regorafenib and pazopanib eye-drops among rats, rabbits and monkeys. Pharmacol. Res. Perspect. 7, e00545 (2019).

    Google Scholar 

  43. Loftsson, T., Hreinsdottir, D. & Stefansson, E. Cyclodextrin microparticles for drug delivery to the posterior segment of the eye: aqueous dexamethasone eye drops. J. Pharm. Pharmacol. 59, 629–635 (2007).

    CAS  Google Scholar 

  44. Ohira, A. et al. Topical dexamethasone γ-cyclodextrin nanoparticle eye drops increase visual acuity and decrease macular thickness in diabetic macular oedema. Acta Ophthalmol. 93, 610–615 (2015).

    CAS  Google Scholar 

  45. Gilger, B. C. Ocular Pharmacology and Toxicology (Humana Press, 2014).

  46. Ruiz-Ederra, J. et al. The pig eye as a novel model of glaucoma. Exp. Eye Res. 81, 561–569 (2005).

    CAS  Google Scholar 

  47. Olsen, T. W., Aaberg, S. Y., Geroski, D. H. & Edelhauser, H. F. Human sclera: thickness and surface area. Am. J. Ophthalmol. 125, 237–241 (1998).

    CAS  Google Scholar 

  48. Vurgese, S., Panda-Jonas, S. & Jonas, J. B. Scleral thickness in human eyes. PLoS ONE 7, e29692 (2012).

    CAS  Google Scholar 

  49. Olsen, T. W., Sanderson, S., Feng, X. & Hubbard, W. C. Porcine sclera: thickness and surface area. Invest. Ophthalmol. Vis. Sci. 43, 2529–2532 (2002).

    Google Scholar 

  50. Struble, C., Howard, S. & Relph, J. Comparison of ocular tissue weights (volumes) and tissue collection techniques in commonly used preclinical animal species. Acta Opthalmol. 92, https://doi.org/10.1111/j.1755-3768.2014.S005.x (2014).

    Google Scholar 

  51. Rajapaksa, T. E. et al. Intranasal M cell uptake of nanoparticles is independently influenced by targeting ligands and buffer ionic strength. J. Biol. Chem. 285, 23739–23746 (2010).

    CAS  Google Scholar 

  52. Ensign, L. M., Hoen, T. E., Maisel, K., Cone, R. A. & Hanes, J. S. Enhanced vaginal drug delivery through the use of hypotonic formulations that induce fluid uptake. Biomaterials 34, 6922–6929 (2013).

    CAS  Google Scholar 

  53. Pihl, L., Wilander, E. & Nylander, O. Comparative study of the effect of luminal hypotonicity on mucosal permeability in rat upper gastrointestinal tract. Acta Physiol. 193, 67–78 (2008).

    CAS  Google Scholar 

  54. Noach, A. B. J. et al. Effect of anisotonic conditions on the transport of hydrophilic model compounds across monolayers of human colonic cell lines. J. Pharmacol. Exp. Ther. 270, 1373–1380 (1994).

    CAS  Google Scholar 

  55. Nance, E. A. et al. A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue. Sci. Transl. Med. 4, 149ra119 (2012).

    Google Scholar 

  56. Wilhelmus, K. R. The draize eye test. Surv. Ophthalmol. 45, 493–515 (2001).

    CAS  Google Scholar 

  57. Wolffsohn, J. S. et al. TFOS DEWS II diagnostic methodology report. Ocul. Surf. 15, 539–574 (2017).

    Google Scholar 

  58. Bron, A. J., Evans, V. E. & Smith, J. A. Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea 22, 640–650 (2003).

    Google Scholar 

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Acknowledgements

The authors thank D. Guyton for sharing his expertise in light refraction, F. Selaru and L. Li for assistance with the swine animal protocol, and the veterinary and husbandry staff for their assistance. This work was supported by the National Institutes of Health (NIH) (grant nos. R01EB016121, R01EY026578 and P30EY001765), the Robert H. Smith Family Foundation, Guerrieri Family Foundation, a Sybil B. Harrington Special Scholar Award and a departmental grant from Research to Prevent Blindness, the KKESH–WEI Collaborative Research Fund, and a Hartwell Foundation Postdoctoral Fellowship. Drug measurements were conducted by the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. The work conducted by the Analytical Pharmacology Core was supported by the NIH grants P30CA006973, S10RR026824 and S10OD020091, as well as grant number UL1TR001079 and UL1TR003098 from the National Center for Advancing Translational Sciences, a component of the NIH, and the NIH Roadmap for Medical Research. This paper and its contents are solely the responsibility of the authors and do not necessarily represent the official view of the National Center for Advancing Translational Sciences or the NIH.

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  1. Abhijit Date

    Present address: The Daniel K. Inouye College of Pharmacy, University of Hawaii Hilo, Hilo, HI, USA

Authors and Affiliations

  1. Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Yoo Chun Kim, Matthew D. Shin, Henry T. Hsueh, Abhijit Date, Hyounkoo Han, Amy Xiao, Youngwook Kim, Laolu Ogunnaike, Donald J. Zack, Justin Hanes & Laura M. Ensign

  2. Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Yoo Chun Kim, Matthew D. Shin, Sean F. Hackett, Raquel Lima e Silva, Abhijit Date, Hyounkoo Han, Byung-Jin Kim, Albert S. Jun, Peter J. McDonnell, Charles Eberhart, Ian Pitha, Donald J. Zack, Peter A. Campochiaro, Justin Hanes & Laura M. Ensign

  3. Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA

    Henry T. Hsueh, Laolu Ogunnaike, Justin Hanes & Laura M. Ensign

  4. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA

    Amy Xiao, Justin Hanes & Laura M. Ensign

  5. Department of Biophysics, Johns Hopkins University, Baltimore, MD, USA

    Youngwook Kim

  6. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA

    Nicole M. Anders, Avelina Hemingway, Ping He, Justin Hanes & Laura M. Ensign

  7. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Justin Hanes & Laura M. Ensign

  8. Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Justin Hanes

  9. Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Laura M. Ensign

  10. Department of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Laura M. Ensign

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Contributions

Y.C.K., M.D.S., S.F.H., A.S.J., P.J.M., D.J.Z., P.A.C., J.H. and L.M.E. designed experiments. Y.C.K., M.S., S.H., H.T.H., R.L.e.S., A.D., H.H, B.-J.K., A.X., Y.K., L.O., N.M.A., A.H., P.H., C.E. and I.P. performed experiments and/or analysed experimental data. Y.C.K., M.S., S.H., B.-J.K., N.M.A., J.H. and L.M.E. wrote sections of the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Justin Hanes or Laura M. Ensign.

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Competing interests

Y.C.K., A.D., L.M.E. and J.H. are inventors on US patent nos. US10092509B2, US10646434B2 and US10485757B2; Australian patent no. AU2016211696B2; Canadian patent no. CA2974715C; and on 11 pending patent applications related to this technology. J.H. and L.E. are founders and have equity in NovusBio LLC. NovusBio LLC intends to develop products using the technology described in this manuscript. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

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Supplementary Video 1

Visualization of the behaviour of 18% iso compared with 12% hypo after administration to conscious rabbits.

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Kim, Y.C., Shin, M.D., Hackett, S.F. et al. Gelling hypotonic polymer solution for extended topical drug delivery to the eye. Nat Biomed Eng 4, 1053–1062 (2020). https://doi.org/10.1038/s41551-020-00606-8

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