Review

.2020 May 10:321:1-22.

doi: 10.1016/j.jconrel.2020.01.057. Epub 2020 Feb 3.

Advances and limitations of drug delivery systems formulated as eye drops

Clotilde Jumelle¹, Shima Gholizadeh², Nasim Annabi³, Reza Dana⁴

Affiliations

¹ Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
² Chemical and Biomolecular Engineering, University of California - Los Angeles, Los Angeles, CA, USA.
³ Chemical and Biomolecular Engineering, University of California - Los Angeles, Los Angeles, CA, USA; Center for Minimally Invasive Therapeutics (C-MIT), California NanoSystems Institute (CNSI), University of California - Los Angeles, Los Angeles, CA, USA. Electronic address: nannabi@ucla.edu.
⁴ Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA. Electronic address: reza_dana@meei.harvard.edu.

PMID:32027938
PMCID: PMC7170772
DOI: 10.1016/j.jconrel.2020.01.057

Review

Advances and limitations of drug delivery systems formulated as eye drops

Clotilde Jumelle et al. J Control Release.2020.

.2020 May 10:321:1-22.

doi: 10.1016/j.jconrel.2020.01.057. Epub 2020 Feb 3.

Authors

Clotilde Jumelle¹, Shima Gholizadeh², Nasim Annabi³, Reza Dana⁴

Affiliations

¹ Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
² Chemical and Biomolecular Engineering, University of California - Los Angeles, Los Angeles, CA, USA.
³ Chemical and Biomolecular Engineering, University of California - Los Angeles, Los Angeles, CA, USA; Center for Minimally Invasive Therapeutics (C-MIT), California NanoSystems Institute (CNSI), University of California - Los Angeles, Los Angeles, CA, USA. Electronic address: nannabi@ucla.edu.
⁴ Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA. Electronic address: reza_dana@meei.harvard.edu.

PMID:32027938
PMCID: PMC7170772
DOI: 10.1016/j.jconrel.2020.01.057

Abstract

Topical instillation of eye drops remains the most common and easiest route of ocular drug administration, representing the treatment of choice for many ocular diseases. Nevertheless, low ocular bioavailability of topically applied drug molecules can considerably limit their efficacy. Over the last several decades, numerous drug delivery systems (DDS) have been developed in order to improve drug bioavailability on the ocular surfaces. This review systematically covers the most recent advances of DDS applicable by topical instillation, that have shown better performance in in vivo models compared to standard eye drop formulations. These delivery systems are based on in situ forming gels, nanoparticles and combinations of both. Most of the DDS have been developed using natural or synthetic polymers. Polymers offer many advantageous properties for designing advanced DDS including biocompatibility, gelation properties and/or mucoadhesiveness. However, despite the high number of studies published over the last decade, there are several limitations for clinical translation of DDS. This review article focuses on the recent advances for the development of ocular drug delivery systems. In addtion, the potential challenges for commercialization of new DDS are presented.

Keywords: Eye drop; Gel; Microparticle; Nanoparticle; Ocular drug delivery; Ocular surface.

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Figures

**Fig. 1.**
Main static and dynamic barriers for ocular drug delivery.

**Fig. 2.. Principle of ‘sol-gel transition’ of different types ofin situ gel used for ocular drug delivery.**
(A) Schematic principle of sol-gel transition of different types of stimuli-responsive materials. Images of sol-gel transition of thermo-responsive PNIPAAm (from [17]) (B) and ion-responsive gellan gum (C) (from [18]).

**Fig. 3.. Sustained drug release and improved therapeutic effect by usingin situ gels compared with conventional eye drops.**
(A) Cumulative amount of pilocarpine released as a function of time from various pilocarpine-containing solutions. All measurements were performed in triplicate, and the standard deviations were all within 3% (From [40]). (B) Decrease in pupil diameter vs time profiles for various pilocarpine-containing solutions. All the measurements were performed in triplicate (From [40]). (C) Thermosensitive PNIPAAm–CS synthesis outline. (D) Morphology change of the PNIPAAm–CS gel forming solution below and upon LCST by using an optical microscope. Scale bar, 20 μm. (E) Timolol maleate concentration in aqueous humor after instillation of 0.5% timolol maleate conventional and thermosensitive PNIPAAm–CS gel forming solution (n=5) (From [43]). (F) The IOP-lowering effect of timolol maleate in thermosensitive PNIPAAm–CS and conventional eye drop (n=4) (From [43]).

**Fig. 4.. Increased drug retention by using poly(lactic acid) (PLA)-based nanoparticle systems.**
(A) Schematic of PLA-Dextran NPs the for the delivery of cyclosporin A (From [127]). (B) Images of rabbit eyes treated with free indocyanine green (ICG), NP–ICG (− PBA), and NP–ICG (+ PBA) obtained with confocal scanning laser ophthalmoscopy, (λ_ex = 795 nm and λ_em = 810 nm). (C) Schematic of PLA-PMA-PBA NPs the for the delivery of cyclosporin A. (D) Slit lamp, fluorescence, and OCT images for LMP-0 (A,E,I), LMP-10 (B,F,J), LMP-30 (C,G,K), and negative control (D,H,L).

**Fig. 5.. Increased drug retention and therapeutic effect using chitosan for the development of polymeric/lipidic NPs.**
(A) Schematic illustration of differently charged lipidic NPs carriers containing dexamethasone (From [105]). (B) The concentration–time curves of timolol (TM) in rabbit tears following topical administration of TM eye drops and liposomes with or without chitosan (CH) (mean ± SD, n = 3) (From [106]). (C) Percentage decrease in intraocular pressure (IOP) after administration of methazolamide solution, methazolamide-SLNs (solid lipids NPs), methazolamide-chitosan-SLNs, commercial eye drops and physical saline solution. (mean ± SD, n = 6) (From [104]).

**Fig. 6.. Increased corneal retention and sustained release of drugs by combiningin situ gels and NPs.**
**(A)** Dynamic gamma scintigraphy study showing percentage radioactivity remaining on cornea with time (blue-diamond shape) marketed, (green triangle shape) chitosanin situ gel, (red-square shape) nanosuspension, (purple-circle shape) nanoparticle ladenin situ gel (From [134]).(B) Concentration of ketarolac in aqueous humor of rabbit eyes with time from the nanodispersion (E2) andin situ gel incorporated with E2 (NG2) compared to Acular® eye drops (From [137]).(C) The difference of IOP between two eyes (i.e. IOP lowering effect) for (a) linear PNIPAAm eye drops; and (b) linear PNIPAAm and nanoparticles mixture eye drops (From [23]).

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