Dry eye disease (DED) is a widespread and frequently reported multifactorial ocular disease that not only causes ocular discomfort but also damages the cornea and conjunctiva. Topical administration is the most common treatment modality for DED. Due to the existence of multiple biological barriers, instilled drugs generally exhibit short action times and poor penetration on the ocular surface. To resolve these issues, several advanced drug delivery systems have been proposed.
Dry eye disease (DED) is a widespread and frequently reported multifactorial ocular disease that not only causes ocular discomfort but also damages the cornea and conjunctiva. Topical administration is the most common treatment modality for DED. Due to the existence of multiple biological barriers, instilled drugs generally exhibit short action times and poor penetration on the ocular surface.
Suspension refers to a liquid formulation formed by dispersing insoluble drug particles in a liquid medium. Common methods for the preparation of suspension include direct dispersion, precipitation, and controlled flocculation. Drug particles in the suspension settle slowly at a rate that does not interfere with correct dosing. They do not agglomerate and can be dispersed evenly through shaking, even after long-term storage. After topical application, drug particles in the suspension can be retained in the cul-de-sac, which leads to prolonged ocular action duration
[28]
[32]
[33] formulated rebamipide particles into an ultrafine state (approximately 640 nm in size) to obtain a highly transparent (light transmittance: 59%) suspension. The duration of blurred vision was thus reduced. Moreover, an in vivo pharmacokinetics study revealed that the concentrations of rebamipide in cornea and conjunctiva were higher than those of conventional suspension, which indicated accelerated absorption rates and improved bioavailability. The particle size and transparency of this suspension remain unchanged for 3 years when stored at 25 °C, which demonstrated its excellent physicochemical stability. Augmenting the mucus-penetrating abilities of drugs represents another strategy to obtain improved outcomes. In this regard, Eysuvis® (Kala Pharmaceuticals, Arlington, MA, USA) is an original loteprednol nanosuspension developed by Kala using the AMPPLIFY mucus-penetrating particle drug delivery technology. This technology permits loteprednol to reach the ocular surface without being degraded in the tear film. A single application of Eysuvis® can increase the concentrations of loteprednol in the aqueous humor, cornea, and conjunctiva by up to three times compared with the commercial product Lotemax® (0.38% loteprednol etabonate eye gel, Bausch & Lomb, Clearwater, FL, USA). Eysuvis® showed high efficacy in DED treatment
[36]. However, the long-term in vivo safety of it remains to be determined.
[37]
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[56]. Ren T et al. formulated adriamycin ion pair loaded liposomes to improve the therapeutic effects of the drug against DED. First, an adriamycin–cholesterol hemisuccinate ion pair was prepared to improve the drug loading. Second, liposomes were prepared by a film hydration method. Finally, the liposomes were sonicated to obtain uniform particle size with high drug loading efficiency
[57]
[35]
[62].
Drug-loaded nanoparticles have also been formulated into dosage forms other than eye drops. For example, Ryu et al. developed nanoparticles incorporated tablets, by embedding PLGA nanoparticles containing dexamethasone in an alginate matrix. The table was applied to the ocular surface using a preocular applicator. It was found that the nanoparticles remained on the ocular surface for up to 2 h. This mode of administration not only improves the bioavailability of drugs but also enables their sterile delivery [63][64]. Nanocapsules are nanoparticles with hollow cores, which are mainly used to deliver labile drugs or engineered for targeted delivery. Although several nanocapsule-based delivery systems exist for anti-inflammatory drugs, few reports are available with respect to their application for the treatment of DED [65][66]. Zhang et al. prepared cyclosporine lipid nanocapsule eye drops with the phase-inversion method, which increased bioavailabilities of cyclosporine in the conjunctiva and cornea. In line with the pharmacokinetic study, superior therapeutic effects over conventional cyclosporine emulsion were observed in pharmacodynamic studies [67].
Other drug delivery systems, such as microspheres, hydrogels, and bioadhesive polymers have also been engineered to improve therapeutic effects of DED drugs. Indeed, promising results are obtained, which have the potential to lead to innovative therapies. Considering the shortcomings of each drug delivery system, the combination of two or more of them deserves further research. Current treatments for DED generally target one aspect of DED pathophysiology. It is fascinating to explore whether superior outcomes can be obtained with drug delivery systems that target multiple aspects simultaneously. There is also a lack of biodegradability and in vivo safety information concerning the above-mentioned drug delivery systems, as most studies are conducted in the short-term setting. A direct comparison between these delivery vehicles represents another issue to be addressed to determine the most suitable one. Finding answers to these questions constitutes the key areas of future research to improve drug delivery for DED.