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


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.

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.


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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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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 methods, figures, tables, video caption and references.

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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).

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