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Review

Engineering Advanced Drug Delivery Systems for Dry Eye: A Review

by
Tian-Zuo Wang
1,2,
Xin-Xin Liu
1,2,
Si-Yu Wang
1,3,
Yan Liu
1,3,
Xin-Yang Pan
1,2,
Jing-Jie Wang
1,2,3,* and
Kai-Hui Nan
1,2,3,*
1
State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou 325027, China
2
National Clinical Research Center for Ocular Diseases, Wenzhou 325027, China
3
National Engineering Research Center of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325027, China
*
Authors to whom correspondence should be addressed.
Bioengineering 2023, 10(1), 53; https://doi.org/10.3390/bioengineering10010053
Submission received: 11 November 2022 / Revised: 12 December 2022 / Accepted: 24 December 2022 / Published: 31 December 2022
(This article belongs to the Topic Advances in Biomaterials)
Browse Figures
Versions Notes

Abstract

:
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. At present, 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. This review discusses new dosage forms of drugs for the treatment of DED in terms of their characteristics and advantages. Innovative formulations that are currently available in the market and under clinical investigation are elaborated. Meanwhile, their deficiencies are discussed. It is envisioned that the flourishing of advanced drug delivery systems will lead to improved management of DED in the near future.

1. Introduction

Dry eye disease (DED) is resulted from decreased tear production, excessive evaporation of tears, or both, ultimately leading to inflammation of the ocular surface [1]. It is manifested by diverse and complex pathological processes. Presently, the association of these processes is not fully established. In 1995, the American Academy of Ophthalmology (AAO) classified DED into two subtypes, namely evaporative dry eye and aqueous-deficient dry eye. However, most patients with DED present symptoms of both subtypes [2]. Epithelial lesions of the ocular surface, inflammation, and neurosensory abnormalities caused by DED can lead to the manifestation of diverse clinical symptoms, such as redness, pain, blurred vision, and sleep disorders. These discomforts not only reduce the patients’ productivity but also seriously affect their quality of life [3,4]. Epidemiological studies reveal that the prevalence of DED is approximately 7% in Europe and America, 12.5–21.6% in Japan and Republic of Korea, and 21–30% in China. In some areas of Russia, the prevalence has been reported to be 40–55% [5,6,7,8,9]. Aging, female gender, prior eye surgery, and widespread use of video terminals have been reported as high-risk factors contributing to the development of DED [10]. China has a huge and aging population, where the prevention and treatment of DED are discouraging. With the significant progress in epidemiological studies of DED in recent years, it is recognized that DED has become an important public health concern [11,12].
Presently, various treatment modalities, such as warm compresses, meibomian gland expression, intranasal tear neurostimulation, contact lenses, and topical medications have been prescribed for DED, among which the topical application of medications represents the most important one [13,14,15,16]. However, multiple biological barriers on the ocular surface, such as the tear film barrier and the corneal and conjunctival barrier, result in rapid drug clearance and low bioavailability. Specifically, the presence of the tear film leads to rapid drug loss and the dense epithelium of the conjunctiva hinders drug entry [17]. Cornea is in fact an amphiphilic tissue, the epithelium layer of which is hydrophobic, so it is difficult for hydrophilic drugs to stay or diffuse. However, if the drug has high lipophilicity, it is difficult for it to penetrate the hydrophilic stromal layer. As a result, drugs must have balanced hydrophilicity and lipophilicity to pass through the entire cornea [18]. These determine that topically applied drugs generally demonstrate extremely low bioavailability. To improve the bioavailability of drugs in the eye, numerous drug delivery systems have been developed (Figure 1) [19,20,21]. For example, nanoparticles are employed to improve the corneal penetration of drugs, hydrogels are employed to extend the retention time of drugs on the ocular surface, and microspheres are employed to achieve sustained release. While eye drops remain the most common delivery vehicles for DED drugs, drug-loaded implants, drug sprays, and microneedles are increasingly being explored. DED is characterized by a vicious cycle triggered by the multifactorial disruption of the ocular surface microenvironment, which leads to inflammation and decreased tear film stability [22]. To ameliorate this chronic condition, long-term treatments are inevitable. However, the long-term use of medications can be associated with serious side effects. The DEWS II report suggests that short-term and long-term treatments should be combined flexibly for different patient conditions to maximize the therapeutic benefits [23]. For patients with mild DED, the use of artificial tears alone can achieve satisfactory therapeutic effects. In contrast, for patients with moderate-to-severe DED, single or multiple drugs are often warranted. As a result, there is an attempt to improve the delivery of drugs with rationally designed drug delivery systems according to the properties of intended drugs and the disease conditions for better outcomes. Some of these delivery systems have led to innovative therapies which are under clinical investigation or even enter the clinic (Table 1) [21,24,25,26,27]. In this contribution, we will elaborate advanced drug delivery systems which are developed for DED. With recent advances in this field, it is expected that improved management of DED can be achieved in the near future.

2. Drug Delivery Systems for DED

2.1. Suspensions

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]. The hydrophobic drugs currently used for the treatment of DED are often administered in this manner.
Alrex® (Bausch & Lomb, Clearwater, FL, USA) is an FDA-approved loteprednol etabonate suspension primarily used as an anti-inflammatory agent. Clinical trials have confirmed that DED can be treated effectively by monotherapy with this drug or combination therapy containing artificial tears [29,30]. Furthermore, suspensions of the immunosuppressant cyclosporine and the mucin-stimulating drug rebamipide have also been approved for treating DED [22,31]. In a randomized multicenter phase III study, 2% rebamipide suspension and 0.1% sodium hyaluronate were randomly instilled in 188 patients with DED, which demonstrated that the 2% rebamipide suspension was more effective in relieving foreign body sensation as well as eye pain [32].
Although rebamipide suspension is advantageous for the treatment of DED, it is a milky liquid and blurs the patient’s vision temporarily, which reduces visual quality. To overcome this shortcoming, Matsuda et al. [33] formulated rebamipide particles into an ultrafine state (approximately 640 nm in size) to obtain a highly transparent (light transmittance: 59%) suspension (Figure 2). 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 [34,35]. Moreover, a multicenter randomized clinical trial demonstrated it was safe and well-tolerated for short-term use (2–4 weeks) [36]. However, the long-term in vivo safety of it remains to be determined.

2.2. Emulsions

Emulsion refers to a two-phase liquid in which the two phases are immiscible with each other. It generally consists of an aqueous phase (denoted by W), an oil phase (denoted by O), and an emulsifier. One phase is dispersed in the other in the form of small droplets, leading to a heterogeneous dispersion. The oil-in-water (O/W) emulsion serves as a good delivery vehicle for hydrophobic ophthalmic drugs, because the oil phase of it can be harnessed to dissolve poorly water-soluble molecules. As a result, improved ocular bioavailability is obtained [37]. Restasis® (Allergan, Waco, TX, USA), an O/W anionic nanoemulsion containing cyclosporine, is the first commercially available ophthalmic emulsion for DED. It is obtained by dissolving cyclosporine in castor oil using polysorbate as the emulsifier. The drug droplets of Restasis® spread easily on the ocular surface after instillation, thus allowing fast drug absorption and onset of action [38]. Emulsions also increase the solubility of hydrophobic drugs and offer ease of scale production in industrial settings [39].
Ikervis® is an O/W cationic nanoemulsion of cyclosporine developed by Santen Pharmaceutical (Osaka, Japan). The drug concentration of Ikervis® is the highest in the clinic. It is used in patients with severe DED that cannot be ameliorated by artificial tears. Because the emulsion droplets in Ikervis® are smaller than those in Restasis®, the penetration of cyclosporine into the cornea is enhanced. Moreover, the unique cationic Ikervis® can interact electrostatically with the negatively charged ocular surface, which prolongs residence time of the drug. The dosing frequency of Ikervis® is one time per day. This has been associated with improved patient compliance and therapeutic efficiency. A good safety profile of Ikervis® had also been demonstrated in a 12-month multicenter double-blind clinical trial [40]. Cationic emulsions are prone to cause local side effects, such as mild pain at the instillation site [41,42]. To improve eye comfort and bioavailability of the drug, Bang et al. developed self-emulsifying nanodrug delivery systems, namely, Cyporin-N (SNEDDS-N; Taejoon Pharma, Seoul, Republic of Korea) and T-sporin (SNEDDS-T; Taejoon Pharma, Seoul, Republic of Korea). SNEDDS is an anhydrous homogeneous mixture of oils, drugs, surfactants, and cosurfactants. Compared with the high turbidity and unstable pH of Restasis®, SNEDDS exhibits more uniform particle sizes, better light transmission, and more stable pH. The ability of SNEDDS to restore tear film stability is also superior to that of Restasis® [43]. Currently, SNEDDS has been developed in a variety of forms and diseases, such as solid SNEDDS, controlled-release SNEDDS, mucus-permeable SNEDDS, and targeted SNEDDS [44,45,46]. It is hoped that these innovative formulations will lead to a breakthrough in the management of DED. Apart from drug-loaded emulsions, drug-free emulsions have also been developed for DED. For instance, Cationorm® from Santen Pharmaceutical is a drug-free O/W cationic nanoemulsion. The benzylcetyldimethylammonium chloride presented in Cationorm® is a cationic surfactant that possesses intrinsic antimicrobial activity, which makes Cationorm® a preservative-free dosage form. This design enhances the safety of Cationorm®. Pharmacodynamic studies revealed that Cationorm® not only exhibited moisturizing and lubricating properties but also stabilized the tear film by its oily components, thus making it a safe and effective tear supplement [47,48].

2.3. Liposomes

Liposomes are tiny vesicles of 10–1000 nm which are consisted of natural or synthetic phospholipid bilayers. They can be classified as small unilamellar vesicles, large unilamellar vesicles, giant unilamellar vesicles, oligolamellar vesicles, multilamellar large vesicles, and multivesicular vesicles [49]. Film hydration, reverse phase evaporation, solvent injection, detergent removal, and the heating method are conventionally used for the preparation of liposomes. Meanwhile, new technologies such as microfluidic methods and the supercritical fluidic method have gained considerable attention [50]. Liposomes improve the delivery of ophthalmic drugs by encapsulating hydrophobic ones in phospholipid bilayers or encapsulating hydrophilic ones in the aqueous core. With similar structure and composition as the cell membrane, liposomes are generally biodegradable and well-tolerated [51,52,53].
The Tears Again® liposome spray developed by Optima Pharmazeutische (Hallbergmoos, Germany) is a new generation of liposome supplements capable of repairing all three layers of the tear film. The phospholipids in the ingredients repair the lipid layer of the tear film, the isotonic solution replenishes the aqueous layer, and the sodium hyaluronate serves as an alternative to the mucus layer. Upon application, the active ingredients are absorbed transdermally. Meanwhile, the preservatives are blocked outside the skin and do not enter the tear film, thereby preventing damage to the eyes. In a double-blind clinical trial, the Tears Again® liposome spray was found to reduce discomfort and stabilize the tear film more efficiently than saline spray and 0.1% sodium hyaluronate [54,55]. In another example, Chen et al. prepared tacrolimus-loaded cationic liposomes using the film hydration method. The resultant formulation prolongs the retention time of FK506 on the ocular surface, increases its concentration in the cornea, and exerts a good therapeutic effect owing to its anti-inflammatory property and ability to promote epithelial cell healing [56]. Ren T et al. formulated adriamycin ion pair loaded liposomes to improve the therapeutic effects of the drug against DED (Figure 3). 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]. Recently, the macromolecular protein lactoferrin and the antioxidant astaxanthin have also been encapsulated in liposomes, which showed favorable therapeutic effects against DED as proved by in vivo pharmacodynamics studies [58,59,60].

2.4. Nanoparticles

Nanoparticles for drug encapsulation are nanosized delivery vehicles with particle sizes in the range of 1–1000 nm. The majority of them in ophthalmic applications are made from natural or synthetic polymers (gelatin, silk fibroin, chitosan, PLGA, PLA, PCL, etc.). Various methods, such as nanoprecipitation, self-assembly, ionic gelation, and desolvation, have been developed for their preparation. Superior therapeutic effects against ocular diseases are obtained via different mechanisms including increasing the dissolution/solubility of poorly water-soluble drugs, affording sustained release, enhancing ocular retention/penetration, or transporting drugs to targeted tissues/cells [35].
The residence time of eye drops is short due to blink and nasolacrimal duct drainage, which lead to low drug bioavailability. To overcome this drawback, Nagai et al. fabricated a rebamipide-based solid nanoparticle formulation (REB-NPs) via grinding. The thus-obtained rebamipide nanoparticles were elliptical, with particle sizes in the range of 40–200 nm. After being applied to the eyelid, rebamipide can be delivered to the tear film through meibomian glands. The rebamipide nanoparticles prolonged the release duration of rebamipide compared with the conventional rebamipide suspension. Thus, increased mucin levels and tear film restoration were obtained [61]. As the vicious cycle of DED is generally accompanied with a series of changes in the ocular surface microenvironment, nanoparticles with dual or multiple functions are likely to produce synergistic effects and lead to improved therapeutic outcomes. Li YJ et al. developed an AF/Au@Poly-CH nanoparticle formulation with anti-inflammatory and antioxidant functions. AF/Au@Poly-CH was obtained via a one-step self-assembly process. In vivo safety and efficacy studies in rabbit eyes revealed that the resultant nanoformulation was well-tolerated and demonstrated high therapeutic efficacy [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].

2.5. Microspheres

Microspheres are micro-sized polymeric or inorganic particles with a spherical geometry, which deliver therapeutic cargoes by adsorbing them on the particle surface or encapsulating them within the particle matrix. They have been fabricated by various techniques, such as emulsion–solvent evaporation, spray drying, phase separation, and ionic gelation, with emulsion–solvent evaporation being the most common one (Figure 4 [68]). Industrial production of microspheres is simple and cost-effective. Moreover, long-term sustained release and modular delivery of multiple drugs for combination therapy can be achieved. For moderate and severe DED, the efficiency of conventional dosage forms of anti-inflammatory drugs is insufficient. Consequently, long-term, frequent dosing of high-concentration dosage forms is required, which destroys immune homeostasis and results in numerous side effects [69]. To solve these problems, Ratay et al. formulated degradable polymer microspheres (TRI) delivering Treg-inducing drugs to stimulate the endogenous production of Treg cells [70]. The microsphere formulation has been shown to be effective in preventing tear loss and maintaining goblet cell density. In addition, it reduces corneal fluorescein staining. However, this formulation is composed of three kinds of microspheres with different drugs, which makes the production and storage of it not cost-effective for practical application [71]. To this end, sulfanilide hydroxamic acid-loaded PLGA microspheres with a similar Treg-inducing function have been prepared [72]. The resultant formulation offers sustained release, inhibits inflammation, and promotes the restoration of immune homeostasis by increasing endogenous Treg cells. As Treg cells are intrinsic components of the immune system, it is expected that this therapeutic strategy will not disturb the immune homeostasis of the patients as conventional anti-inflammatory therapies. Although the microspheres represent a promising delivery system for DED drugs, the drawbacks of low encapsulation efficiency, poor stability, and burst release of drugs remain to be resolved.

2.6. Micelles

Micelles represent a class of drug delivery vehicles formulated with surfactants or amphiphilic polymers, the structure of which is characterized by a hydrophilic shell and a hydrophobic core. Therefore, hydrophobic drugs can be encapsulated in the cores for improved therapeutic effects. In regard to ocular drug delivery, the adhesive properties of polymeric micelles can prolong the residence time of drugs on the ocular surface, whereas their small sizes enhance the tissue penetration performance of drugs [73]. Notably, the aqueous solution of micelles is generally transparent, which will not interfere with the patient’s vision after application. Common techniques for micelle preparation include thin-film hydration, dialysis, lyophilization, and emulsion [74]. Micelles with uniform particle sizes can be obtained when the concentrations of surfactants or amphiphilic polymers reach their critical micelle concentrations. The high loading efficiency and ease of surface modification make micelles particularly appealing for ocular drug delivery [75,76]. Cequa® is a micellar eye drop formulation of cyclosporine developed by Sun Pharmaceutical (Mumbai, India). By encapsulating the hydrophobic drug in micelles of 12–20 nm, the concentration of dissolved cyclosporine in the eye drop is greatly increased. The lyophilized powder of Cequa® is stable for at least 3 months. Moreover, it was reported that the micelle formulation showed a 4.5-fold increase in ocular retention compared to the 0.05% cyclosporine emulsion [77]. Due to improved physicochemical stability and tissue penetration ability of cyclosporine, increased bioavailability was obtained [78]. It should be noted that the safety of Cequa® was only evaluated in a 12-week study, which was much shorter than the conventional 12-month DED treatment duration [79]. Therefore, the long-term safety of Cequa® for DED warrants further clinical evaluation. In addition to the above-mentioned marketed micelle-based formulation, micelles with dual therapeutic effects have also been developed. As shown in Figure 5, Li S et al. fabricated losmapimod-loaded polymeric micelles with cationic amphiphilic antioxidant peptides by the dialysis method. The thus-obtained formulation possessed anti-inflammatory and antioxidant activities. Ex vivo and in vivo studies revealed that it was safe for ocular application and demonstrated impressive therapeutic effects [80]. Therefore, designing multifunctional micellar drug delivery systems targeting several aspects of DED pathogenesis represents a promising direction to develop innovative therapies for DED.

2.7. Bioadhesive Polymers

Bioadhesion, in the pharmaceutical context, refers to a scenario in which certain high molecular polymers adhere on the mucous membranes of the mouth, nose, eye, vagina, or digestive tract [81]. The moist atmosphere of the mucous membranes can result in the swelling of bioadhesive polymers, which interpenetrate with the mucus subsequently and lead to extended tissue adhesion. This phenomenon has been widely used to prolong the in vivo residence time of drugs [82]. Most of currently used bioadhesive polymers are biodegradable and biocompatible. Furthermore, many of them have lubricant and hygroscopic properties, which aid in ameliorating the dryness of DED [83]. Bioadhesive polymers are not only used alone in monotherapies of DED, but also used as adjuvants in combination therapies. In addition, they have been employed as matrix materials to formulate other drug delivery vehicles for DED, such as nanoparticles, hydrogels, and liposomes [84,85]. Table 2 presents common bioadhesive polymers used for the management of DED. Apart from conventional bioadhesive polymers, there are also attempts to develop new bioadhesive compositions, for example, GlicoPro® is an eye drop formulation based on snail mucus extracts, which demonstrates superior bioadhesive properties over sodium hyaluronate. It not only promotes corneal wound healing, but also exerts anti-inflammatory and analgesic effects [86]. Despite the promising observations, further safety and efficacy evaluations with respect to GlicoPro® are warranted. In another attempt, Liu et al. designed cationized hyaluronic acid-coated spanlastics (CHASV) for ocular delivery of cyclosporine. CHASV demonstrates favorable wettability and bioadhesive properties, as well as offers sustained release of cyclosporine to the ocular surface, which is associated with improved therapeutic outcomes against DED. This novel formulation serves as an appealing alternative to commercial cyclosporine emulsions for the treatment of DED in the future [87].

2.8. Hydrogels

Hydrogels are a class of water-swollen network structures with high water content and mechanical properties mimicking the extracellular matrix and soft tissues. Therefore, they have received considerable attention in drug delivery and tissue engineering. Hydrogels are traditionally formulated by physical or covalent cross-linking of hydrophilic polymers [88]. Nowadays, there are also increasing instances of hydrogels obtained from the self-assembly of small molecules. As for DED, in situ gels and ocular implants are among the most common subtypes of hydrogels for drug delivery. The viscous properties of in situ gels can be harnessed to prolong the ocular residence time of drugs. On the other hand, ocular implants, such as contact lenses, serve as drug reservoirs to provide sustained release.

2.8.1. In Situ Gels

In situ gels are a class of hydrogels that undergo sol–gel transition after in vivo application. They are also known as smart hydrogels as the phase transition can be triggered by various physiological signals, such as temperature, pH, or ions in the tear fluid [89]. The sol–gel transition leads to a bioadhesive network that fixes the drugs on the ocular surface, which prolongs ocular retention and facilitates sustained release. A recent study revealed that levocarnitine delivered by in situ gels showed superior therapeutic effects against DED [90]. Han Y et al. encapsulated FK506 in a thermos-responsive in situ gel formulated with POSS, PEG, and PPG (Figure 6). The resultant formulation was biocompatible. Moreover, prolonged ocular retention and enhanced therapeutic efficiency were demonstrated in a mouse DED model [91]. Eldesouky et al. developed a thermosensitive in situ gel containing lipid nanocapsules loaded with cyclosporine. This dosage form can not only prolong the ocular retention of cyclosporine, but also enhance its tissue penetration ability. A further pharmacodynamic study revealed it outperformed the commercial cyclosporine nanoemulsion in restoring tear production of DED rabbits [92]. The work of Eldesouky et al. provides a promising alternative for DED. However, the use of surfactants and organic solvents during hydrogel fabrication may cause irritation. Therefore, the biocompatibility of this dosage form should be evaluated thoroughly for its successful clinical application.

2.8.2. Hydrogel Implants

Hydrogels have long been used for the fabrication of ocular implants, such as punctal plugs and contact lenses, which also serve as versatile drug delivery vehicles to improve the convenience and effectiveness of DED treatments [19,93]. Gupta et al. developed a cyclosporine-releasing punctal plug with a cylindrical ethyl methacrylate core (Figure 7) [94]. This drug delivery device treats DED through two mechanisms (anti-inflammation and inhibiting tear clearance), thereby providing the patients with a simple and efficient treatment modality. However, the drug in the punctal plug depleted rapidly with low bioavailability. To address this, further efforts have been made by encapsulating drugs in nanocapsules or nanomicelles before embedding them in punctal plugs [95]. Due to the fact that the anatomy of lacrimal ducts varies from person to person, pre-formed punctal plugs are disadvantageous from the perspective of precision medicine. Indeed, complications are frequently reported when the punctal plug does not fit the lacrimal duct of the patient. Xie et al. [96] invented a hyaluronic acid-based in situ punctal plug containing drug-loaded microcapsules. This punctal plug was formed after in vivo injection, thereby fitting lacrimal ducts with different anatomy and circumventing complications associated with conventional punctal plugs. Contact lenses offer another approach for the delivery of DED drugs. To achieve drug encapsulation, the contact lenses are generally dipped in the corresponding drug solution [97,98]. However, this is associated with rapid drug release. Furthermore, some of the encapsulated drugs may make the contact lenses opaque and reduce visual quality. To address these drawbacks, ring-shaped contact lenses have recently been developed, which encapsulate the drug in nanoparticles and deliver it with a ring-shaped boundary region of the contact lenses. For example, prolonged ocular retention and sustained release of hyaluronic acid had been demonstrated with this strategy [99]. It is anticipated that the nanoparticle-encapsulating contact lenses will lead to various innovative therapies for DED.

2.9. Others

The anhydrous drug delivery technology (EyesolTM) developed by Novaliq (Baden-Wurttemberg, Germany) is a proprietary technology that eliminates the use of water, oils, surfactants, or preservatives. Hydrophobic drugs can be dissolved easily in the anhydrous solvent to obtain a drug solution that spreads rapidly on the ocular surface to minimize visual disturbances. NOV 03® and CyclASol®, two products formulated by this technology, have entered clinical trials. NOV 03® is a single-component eye drop of perfluorohexyloctane. It can penetrate the meibomian glands and dissolve the secretions, thereby stabilizing the lipid layer of tear film [100,101,102]. CyclASol® is developed for aqueous-deficient DED by dissolving cyclosporine in EyesolTM [103]. Wirta et al. [104] conducted a phase 2 clinical study to evaluate the efficacy, safety, and tolerability of CyclASol® at two different concentrations (0.1% and 0.05% cyclosporine), which revealed that CyclASol® relieved DED symptoms more rapidly than Restasis® and was associated with better outcomes. Based on these promising results, this product is likely to obtain regulatory approval in the near future.

3. Conclusions

Various drug delivery systems, particularly suspensions, emulsions, liposomes, nanoparticles, microspheres, hydrogels, and bioadhesive polymers, have been engineered to improve the 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 of DED pathophysiology 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 the above-mentioned 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.

Funding

This research was funded by the Major Science and Technology Program of Wenzhou City [Grant number: ZS2017015] and the School of Ophthalmology and Optometry, Wenzhou Medical University [Grant number: J02-20190202, YNZD2201901]. The APC was funded by YNZD2201901.

Data Availability Statement

All data is contained within the article.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Hakim, F.; Farooq, A. Dry Eye Disease: An Update in 2022. JAMA 2022, 327, 478–479. [Google Scholar] [CrossRef] [PubMed]
  2. Messmer, E. The pathophysiology, diagnosis, and treatment of dry eye disease. Dtsch. Arztebl. Int. 2015, 112, 71–81. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Tsubota, K.; Pflugfelder, S.; Liu, Z.; Baudouin, C.; Kim, H.; Messmer, E.; Kruse, F.; Liang, L.; Carreno-Galeano, J.; Rolando, M.; et al. Defining Dry Eye from a Clinical Perspective. Int. J. Mol. Sci. 2020, 21, 9271. [Google Scholar] [CrossRef] [PubMed]
  4. Han, K.-T.; Nam, J.H.; Park, E.-C. Do Sleep Disorders Positively Correlate with Dry Eye Syndrome? Results of National Claim Data. Int. J. Environ. Res. Public Health 2019, 16, 878. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Schaumberg, D.; Dana, R.; Buring, J.; Sullivan, D. Prevalence of dry eye disease among US men: Estimates from the Physicians’ Health Studies. Arch. Ophthalmol. 2009, 127, 763–768. [Google Scholar] [CrossRef] [Green Version]
  6. Lee, J.-H.; Lee, W.; Yoon, J.-H.; Seok, H.; Roh, J.; Won, J.-U. Relationship between symptoms of dry eye syndrome and occupational characteristics: The Korean National Health and Nutrition Examination Survey 2010–2012. BMC Ophthalmol. 2015, 15, 147. [Google Scholar] [CrossRef] [Green Version]
  7. Uchino, M.; Nishiwaki, Y.; Michikawa, T.; Shirakawa, K.; Kuwahara, E.; Yamada, M.; Dogru, M.; Schaumberg, D.A.; Kawakita, T.; Takebayashi, T.; et al. Prevalence and Risk Factors of Dry Eye Disease in Japan: Koumi Study. Ophthalmology 2011, 118, 2361–2367. [Google Scholar] [CrossRef]
  8. Maychuk, D.Y.; Anisimova, S.; Kapkova, S.; Kachanov, A.; Korotkikh, S.; Seleznev, A.; Sakhnov, S.; Leonova, E.; Krylov, S. Prevalence and severity of dry eye in candidates for laser in situ keratomileusis for myopia in Russia. J. Cataract Refract. Surg. 2016, 42, 427–434. [Google Scholar] [CrossRef] [Green Version]
  9. Wu, H.-X.; Xia, X.; Liu, K.; Zheng, Z.; Zhu, N.-Q.; Xu, X.; Gu, Q. Effect of insulin on VEGF expression in bovine retinal microvascular endothelial cells exposed to normal or high glucose. [Zhonghua Yan Ke Za Zhi] Chin. J. Ophthalmol. 2008, 44, 640–644. [Google Scholar]
  10. Li, J.; Zheng, K.; Deng, Z.; Zheng, J.; Ma, H.; Sun, L.; Chen, W. Prevalence and Risk Factors of Dry Eye Disease Among a Hospital-Based Population in Southeast China. Eye Contact Lens Sci. Clin. Pract. 2015, 41, 44–50. [Google Scholar] [CrossRef]
  11. Stapleton, F.; Alves, M.; Bunya, V.Y.; Jalbert, I.; Lekhanont, K.; Malet, F.; Na, K.-S.; Schaumberg, D.; Uchino, M.; Vehof, J.; et al. TFOS DEWS II epidemiology report. Ocul. Surf. 2017, 15, 334–365. [Google Scholar] [CrossRef] [PubMed]
  12. Wang, M.T.M.; Craig, J.P. Core Outcome Sets for Clinical Trials in Dry Eye Disease. JAMA Ophthalmol. 2018, 136, 1180–1181. [Google Scholar] [CrossRef] [PubMed]
  13. O’Neil, E.C.; Henderson, M.; Massaro-Giordano, M.; Bunya, V.Y. Advances in dry eye disease treatment. Curr. Opin. Ophthalmol. 2019, 30, 166–178. [Google Scholar] [CrossRef] [PubMed]
  14. Thulasi, P.; Djalilian, A.R. Update in Current Diagnostics and Therapeutics of Dry Eye Disease. Ophthalmology 2017, 124, S27–S33. [Google Scholar] [CrossRef]
  15. Dosmar, E.; Walsh, J.; Doyel, M.; Bussett, K.; Oladipupo, A.; Amer, S.; Goebel, K. Targeting Ocular Drug Delivery: An Examination of Local Anatomy and Current Approaches. Bioengineering 2022, 9, 41. [Google Scholar] [CrossRef] [PubMed]
  16. Subrizi, A.; del Amo, E.M.; Korzhikov-Vlakh, V.; Tennikova, T.; Ruponen, M.; Urtti, A. Design principles of ocular drug delivery systems: Importance of drug payload, release rate, and material properties. Drug Discov. Today 2019, 24, 1446–1457. [Google Scholar] [CrossRef] [PubMed]
  17. Awwad, S.; Ahmed, A.H.A.M.; Sharma, G.; Heng, J.S.; Khaw, P.T.; Brocchini, S.; Lockwood, A. Principles of pharmacology in the eye. Br. J. Pharmacol. 2017, 174, 4205–4223. [Google Scholar] [CrossRef] [Green Version]
  18. Nasir, N.A.A.; Agarwal, P.; Agarwal, R.; Iezhitsa, I.; Alyautdin, R.; Nukolova, N.N.; Chekhonin, V.P.; Ismail, N.M. Intraocular distribution of topically applied hydrophilic and lipophilic substances in rat eyes. Drug Deliv. 2016, 23, 2765–2771. [Google Scholar] [CrossRef]
  19. Holland, E.J.; Darvish, M.; Nichols, K.K.; Jones, L.; Karpecki, P.M. Efficacy of topical ophthalmic drugs in the treatment of dry eye disease: A systematic literature review. Ocul. Surf. 2019, 17, 412–423. [Google Scholar] [CrossRef]
  20. Yellepeddi, V.K.; Sheshala, R.; McMillan, H.; Gujral, C.; Jones, D.; Singh, T.R.R. Punctal plug: A medical device to treat dry eye syndrome and for sustained drug delivery to the eye. Drug Discov. Today 2015, 20, 884–889. [Google Scholar] [CrossRef] [Green Version]
  21. Nosch, D.S.; Joos, R.E.; Job, M. Prospective randomized study to evaluate the efficacy and tolerability of Ectoin® containing Eye Spray (EES09) and comparison to the liposomal Eye Spray Tears Again® (TA) in the treatment of dry eye disease. Contact Lens Anterior Eye 2021, 44, 101318. [Google Scholar] [CrossRef] [PubMed]
  22. Pflugfelder, S.; de Paiva, C. The Pathophysiology of Dry Eye Disease: What We Know and Future Directions for Research. Ophthalmology 2017, 124, S4–S13. [Google Scholar] [CrossRef] [PubMed]
  23. Şimşek, C.; Doğru, M.; Kojima, T.; Tsubota, K. Current Management and Treatment of Dry Eye Disease. Turk. J. Ophthalmol. 2018, 48, 309–313. [Google Scholar] [CrossRef]
  24. Molokhia, S.A.; Thomas, S.C.; Garff, K.J.; Mandell, K.J.; Wirostko, B.M. Anterior Eye Segment Drug Delivery Systems: Current Treatments and Future Challenges. J. Ocul. Pharmacol. Ther. 2013, 29, 92–105. [Google Scholar] [CrossRef] [PubMed]
  25. Yellepeddi, V.; Palakurthi, S. Recent Advances in Topical Ocular Drug Delivery. J. Ocul. Pharmacol. Ther. 2016, 32, 67–82. [Google Scholar] [CrossRef]
  26. Baino, F.; Kargozar, S. Regulation of the Ocular Cell/Tissue Response by Implantable Biomaterials and Drug Delivery Systems. Bioengineering 2020, 7, 65. [Google Scholar] [CrossRef] [PubMed]
  27. de Paiva, C.; Pflugfelder, S.; Ng, S.; Akpek, E. Topical cyclosporine A therapy for dry eye syndrome. Cochrane Database Syst. Rev. 2019, 9, Cd010. [Google Scholar] [CrossRef]
  28. Bron, A.; de Paiva, C.; Chauhan, S.; Bonini, S.; Gabison, E.; Jain, S.; Knop, E.; Markoulli, M.; Ogawa, Y.; Perez, V.; et al. TFOS DEWS II pathophysiology report. Ocul. Surf. 2017, 15, 438–510. [Google Scholar] [CrossRef]
  29. Beckman, K.; Katz, J.; Majmudar, P.; Rostov, A. Loteprednol Etabonate for the Treatment of Dry Eye Disease. J. Ocul. Pharmacol. Ther. 2020, 36, 497–511. [Google Scholar] [CrossRef]
  30. Wan, P.-X.; Wang, X.-R.; Song, Y.-Y.; Li, Z.-Y.; Duan, H.-C.; Zhang, W.; Liu, Z.; Wang, Z.-C. Study on the treatment of dry eye with Loteprednol Etabonate. [Zhonghua Yan Ke Za Zhi] Chin. J. Ophthalmol. 2012, 48, 142–147. [Google Scholar]
  31. Kashima, T.; Akiyama, H.; Kishi, S.; Itakura, H. Rebamipide ophthalmic suspension for the treatment of dry eye syndrome: A critical appraisal. Clin. Ophthalmol. 2014, 8, 1003–1010. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Kinoshita, S.; Oshiden, K.; Awamura, S.; Suzuki, H.; Nakamichi, N.; Yokoi, N. A Randomized, Multicenter Phase 3 Study Comparing 2% Rebamipide (OPC-12759) with 0.1% Sodium Hyaluronate in the Treatment of Dry Eye. Ophthalmology 2013, 120, 1158–1165. [Google Scholar] [CrossRef] [PubMed]
  33. Matsuda, T.; Hiraoka, S.; Urashima, H.; Ogura, A.; Ishida, T. Preparation of an Ultrafine Rebamipide Ophthalmic Suspension with High Transparency. Biol. Pharm. Bull. 2017, 40, 665–674. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Paton, D. Loteprednol etabonate: A formulation for short-term use in inflammatory flares in dry eye disease. Drugs Today 2022, 58, 77. [Google Scholar] [CrossRef] [PubMed]
  35. Meng, T.; Kulkarni, V.; Simmers, R.; Brar, V.; Xu, Q. Therapeutic implications of nanomedicine for ocular drug delivery. Drug Discov. Today 2019, 24, 1524–1538. [Google Scholar] [CrossRef]
  36. Korenfeld, M.; Nichols, K.K.O.; Goldberg, D.; Evans, D.O.; Sall, K.; Foulks, G.; Coultas, S.; Brazzell, K. Safety of KPI-121 Ophthalmic Suspension 0.25% in Patients with Dry Eye Disease: A Pooled Analysis of 4 Multicenter, Randomized, Vehicle-Controlled Studies. Cornea 2021, 40, 564–570. [Google Scholar] [CrossRef]
  37. Yamaguchi, M.; Yasueda, S.-I.; Isowaki, A.; Yamamoto, M.; Kimura, M.; Inada, K.; Ohtori, A. Formulation of an ophthalmic lipid emulsion containing an anti-inflammatory steroidal drug, difluprednate. Int. J. Pharm. 2005, 301, 121–128. [Google Scholar] [CrossRef]
  38. Lallemand, F.; Felt-Baeyens, O.; Besseghir, K.; Behar-Cohen, F.; Gurny, R. Cyclosporine A delivery to the eye: A pharmaceutical challenge. Eur. J. Pharm. Biopharm. 2003, 56, 307–318. [Google Scholar] [CrossRef]
  39. Singh, B.; Beg, S.; Khurana, R.K.; Sandhu, P.S.; Kaur, R.; Katare, O.P. Recent advances in self-emulsifying drug delivery systems (SEDDS). Crit. Rev. Ther. Drug Carr. Syst. 2014, 31, 121–185. [Google Scholar] [CrossRef]
  40. Baudouin, C.; De La Maza, M.S.; Amrane, M.; Garrigue, J.-S.; Ismail, D.; Figueiredo, F.C.; Leonardi, A. One-Year Efficacy and Safety of 0.1% Cyclosporine a Cationic Emulsion in the Treatment of Severe Dry Eye Disease. Eur. J. Ophthalmol. 2017, 27, 678–685. [Google Scholar] [CrossRef] [Green Version]
  41. Leonardi, A.; Van Setten, G.; Amrane, M.; Ismail, D.; Garrigue, J.-S.; Figueiredo, F.C.; Baudouin, C. Efficacy and Safety of 0.1% Cyclosporine a Cationic Emulsion in the Treatment of Severe Dry Eye Disease: A Multicenter Randomized Trial. Eur. J. Ophthalmol. 2016, 26, 287–296. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Hoy, S.M. Ciclosporin Ophthalmic Emulsion 0.1%: A Review in Severe Dry Eye Disease. Drugs 2017, 77, 1909–1916. [Google Scholar] [CrossRef] [PubMed]
  43. Bang, S.P.; Yeon, C.Y.; Adhikari, N.; Neupane, S.; Kim, H.; Lee, D.C.; Son, M.J.; Lee, H.G.; Kim, J.-Y.; Jun, J.H. Cyclosporine A eyedrops with self-nanoemulsifying drug delivery systems have improved physicochemical properties and efficacy against dry eye disease in a murine dry eye model. PLoS ONE 2019, 14, e0224805. [Google Scholar] [CrossRef] [Green Version]
  44. Nazlı, H.; Mesut, B.; Özsoy, Y. In Vitro Evaluation of a Solid Supersaturated Self Nanoemulsifying Drug Delivery System (Super-SNEDDS) of Aprepitant for Enhanced Solubility. Pharmaceuticals 2021, 14, 1089. [Google Scholar] [CrossRef] [PubMed]
  45. Rasoanirina, B.N.V.; Lassoued, M.A.; Kamoun, A.; Bahloul, B.; Miladi, K.; Sfar, S. Voriconazole-loaded self-nanoemulsifying drug delivery system (SNEDDS) to improve transcorneal permeability. Pharm. Dev. Technol. 2020, 25, 694–703. [Google Scholar] [CrossRef] [PubMed]
  46. Arshad, R.; Tabish, T.; Kiani, M.; Ibrahim, I.; Shahnaz, G.; Rahdar, A.; Kang, M.; Pandey, S. A Hyaluronic Acid Functionalized Self-Nano-Emulsifying Drug Delivery System (SNEDDS) for Enhancement in Ciprofloxacin Targeted Delivery against Intracellular Infection. Nanomaterials 2021, 11, 1086. [Google Scholar] [CrossRef]
  47. Amrane, M.; Creuzot-Garcher, C.; Robert, P.-Y.; Ismail, D.; Garrigue, J.-S.; Pisella, P.-J.; Baudouin, C. Ocular tolerability and efficacy of a cationic emulsion in patients with mild to moderate dry eye disease—A randomised comparative study. J. Fr. Ophtalmol. 2014, 37, 589–598. [Google Scholar] [CrossRef]
  48. Lyseng-Williamson, K.A. Cationorm® (cationic emulsion eye drops) in dry eye disease: A guide to its use. Drugs Ther. Perspect. 2016, 32, 317–322. [Google Scholar] [CrossRef]
  49. Nkanga, C.I.; Bapolisi, A.M.; Okafor, N.I.; Krause, R.W.M. General Perception of Liposomes: Formation, Manufacturing and Applications. In Liposomes-Advances and Perspectives; IntechOpen: Rijeka, Croatia, 2019. [Google Scholar] [CrossRef] [Green Version]
  50. Liang, W.; Levchenko, T.S.; Torchilin, V.P. Encapsulation of ATP into liposomes by different methods: Optimization of the procedure. J. Microencapsul. 2004, 21, 251–261. [Google Scholar] [CrossRef] [PubMed]
  51. Guimarães, D.; Cavaco-Paulo, A.; Nogueira, E. Design of liposomes as drug delivery system for therapeutic applications. Int. J. Pharm. 2021, 601, 120571. [Google Scholar] [CrossRef]
  52. López-Cano, J.; González-Cela-Casamayor, M.; Andrés-Guerrero, V.; Herrero-Vanrell, R.; Molina-Martínez, I. Liposomes as vehicles for topical ophthalmic drug delivery and ocular surface protection. Expert Opin. Drug Deliv. 2021, 18, 819–847. [Google Scholar] [CrossRef] [PubMed]
  53. Agarwal, R.; Iezhitsa, I.; Agarwal, P.; Nasir, N.A.A.; Razali, N.; Alyautdin, R.; Ismail, N.M. Liposomes in topical ophthalmic drug delivery: An update. Drug Deliv. 2016, 23, 1075–1091. [Google Scholar] [CrossRef]
  54. Craig, J.P.; Purslow, C.; Murphy, P.J.; Wolffsohn, J.S. Effect of a liposomal spray on the pre-ocular tear film. Contact Lens Anterior Eye 2010, 33, 83–87. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Khaireddin, R.; Schmidt, K. Comparative investigation of treatments for evaporative dry eye. Klin. Mon. Augenheilkd. 2010, 227, 128–134. [Google Scholar] [CrossRef] [PubMed]
  56. Chen, X.; Wu, J.; Lin, X.; Wu, X.; Yu, X.; Wang, B.; Xu, W. Tacrolimus Loaded Cationic Liposomes for Dry Eye Treatment. Front. Pharmacol. 2022, 13, 838168. [Google Scholar] [CrossRef]
  57. Ren, T.; Lin, X.; Zhang, Q.; You, D.; Liu, X.; Tao, X.; Gou, J.; Zhang, Y.; Yin, T.; He, H.; et al. Encapsulation of Azithromycin Ion Pair in Liposome for Enhancing Ocular Delivery and Therapeutic Efficacy on Dry Eye. Mol. Pharm. 2018, 15, 4862–4871. [Google Scholar] [CrossRef]
  58. López-Machado, A.; Díaz-Garrido, N.; Cano, A.; Espina, M.; Badia, J.; Baldomà, L.; Calpena, A.C.; Souto, E.B.; García, M.L.; Sánchez-López, E. Development of Lactoferrin-Loaded Liposomes for the Management of Dry Eye Disease and Ocular Inflammation. Pharmaceutics 2021, 13, 1698. [Google Scholar] [CrossRef]
  59. Shimokawa, T.; Fukuta, T.; Inagi, T.; Kogure, K. Protective effect of high-affinity liposomes encapsulating astaxanthin against corneal disorder in the in vivo rat dry eye disease model. J. Clin. Biochem. Nutr. 2020, 66, 224–232. [Google Scholar] [CrossRef] [Green Version]
  60. Shimokawa, T.; Yoshida, M.; Fukuta, T.; Tanaka, T.; Inagi, T.; Kogure, K. Efficacy of high-affinity liposomal astaxanthin on up-regulation of age-related markers induced by oxidative stress in human corneal epithelial cells. J. Clin. Biochem. Nutr. 2019, 64, 27–35. [Google Scholar] [CrossRef] [Green Version]
  61. Nagai, N.; Ishii, M.; Seiriki, R.; Ogata, F.; Otake, H.; Nakazawa, Y.; Okamoto, N.; Kanai, K.; Kawasaki, N. Novel Sustained-Release Drug Delivery System for Dry Eye Therapy by Rebamipide Nanoparticles. Pharmaceutics 2020, 12, 155. [Google Scholar] [CrossRef] [Green Version]
  62. Li, Y.-J.; Luo, L.-J.; Harroun, S.G.; Wei, S.-C.; Unnikrishnan, B.; Chang, H.-T.; Huang, Y.-F.; Lai, J.-Y.; Huang, C.-C. Synergistically dual-functional nano eye-drops for simultaneous anti-inflammatory and anti-oxidative treatment of dry eye disease. Nanoscale 2019, 11, 5580–5594. [Google Scholar] [CrossRef] [PubMed]
  63. Ryu, W.M.; Kim, S.-N.; Min, C.H.; Bin Choy, Y. Dry Tablet Formulation of PLGA Nanoparticles with a Preocular Applicator for Topical Drug Delivery to the Eye. Pharmaceutics 2019, 11, 651. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Coursey, T.G.; Henriksson, J.T.; Marcano, D.C.; Shin, C.S.; Isenhart, L.C.; Ahmed, F.; De Paiva, C.S.; Pflugfelder, S.C.; Acharya, G. Dexamethasone nanowafer as an effective therapy for dry eye disease. J. Control Release 2015, 213, 168–174. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Rebibo, L.; Tam, C.; Sun, Y.; Shoshani, E.; Badihi, A.; Nassar, T.; Benita, S. Topical tacrolimus nanocapsules eye drops for therapeutic effect enhancement in both anterior and posterior ocular inflammation models. J. Control Release 2021, 333, 283–297. [Google Scholar] [CrossRef]
  66. Hu, Q.; Wu, W.; Wang, M.; Shao, S.; Jin, P.; Chen, Q.; Bai, H.; Zhao, X.; Huang, J.; Wang, J.; et al. Reverting chemoresistance of targeted agents by a ultrasoluble dendritic nanocapsule. J. Control Release 2020, 317, 67–77. [Google Scholar] [CrossRef]
  67. Zhang, R.; Sun, M.; Ran, Y.; Deng, Y.; Ge, Y.; Zhu, X.; Tao, L.; Shang, J.; Gou, H.; He, T.; et al. A Novel Eyes Topical Drug Delivery System: CsA-LNC for the Treatment of DED. Pharm. Res. 2020, 37, 146. [Google Scholar] [CrossRef]
  68. Su, Y.; Zhang, B.; Sun, R.; Liu, W.; Zhu, Q.; Zhang, X.; Wang, R.; Chen, C. PLGA-based biodegradable microspheres in drug delivery: Recent advances in research and application. Drug Deliv. 2021, 28, 1397–1418. [Google Scholar] [CrossRef]
  69. Doutre, M.S. Ciclosporin. Ann. Dermatol. Venereol. 2002, 129, 392–404. [Google Scholar] [PubMed]
  70. Ratay, M.L.; Balmert, S.C.; Acharya, A.P.; Greene, A.C.; Meyyappan, T.; Little, S.R. TRI Microspheres prevent key signs of dry eye disease in a murine, inflammatory model. Sci. Rep. 2017, 7, 17527. [Google Scholar] [CrossRef] [Green Version]
  71. Ratay, M.L.; Glowacki, A.J.; Balmert, S.C.; Acharya, A.P.; Polat, J.; Andrews, L.P.; Fedorchak, M.V.; Schuman, J.S.; Vignali, D.A.; Little, S.R. Treg-recruiting microspheres prevent inflammation in a murine model of dry eye disease. J. Control Release 2017, 258, 208–217. [Google Scholar] [CrossRef]
  72. Ratay, M.L.; Balmert, S.; Bassin, E.J.; Little, S.R. Controlled release of an HDAC inhibitor for reduction of inflammation in dry eye disease. Acta Biomater. 2018, 71, 261–270. [Google Scholar] [CrossRef] [PubMed]
  73. Durgun, M.; Güngör, S.; Özsoy, Y. Micelles: Promising Ocular Drug Carriers for Anterior and Posterior Segment Diseases. J. Ocul. Pharmacol. Ther. 2020, 36, 323–341. [Google Scholar] [CrossRef] [PubMed]
  74. Kumar, M.; Kaushal, N.; Singh, A.; Tiwari, A.; Tiwari, V.; Pahwa, R. A Review on Polymeric Nanostructured Micelles for the Ocular Inflammation—Main Emphasis on Uveitis. Pharm. Nanotechnol. 2022. [Google Scholar] [CrossRef] [PubMed]
  75. Ghezzi, M.; Pescina, S.; Padula, C.; Santi, P.; Del Favero, E.; Cantù, L.; Nicoli, S. Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions. J. Control Release 2021, 332, 312–336. [Google Scholar] [CrossRef]
  76. Mandal, A.; Bisht, R.; Rupenthal, I.D.; Mitra, A.K. Polymeric micelles for ocular drug delivery: From structural frameworks to recent preclinical studies. J. Control Release 2017, 248, 96–116. [Google Scholar] [CrossRef] [Green Version]
  77. Yu, Y.; Chen, D.; Li, Y.; Yang, W.; Tu, J.; Shen, Y. Improving the topical ocular pharmacokinetics of lyophilized cyclosporine A-loaded micelles: Formulation, in vitro and in vivo studies. Drug Deliv. 2018, 25, 888–899. [Google Scholar] [CrossRef] [Green Version]
  78. Mandal, A.; Gote, V.; Pal, D.; Ogundele, A.; Mitra, A.K. Ocular Pharmacokinetics of a Topical Ophthalmic Nanomicellar Solution of Cyclosporine (Cequa®) for Dry Eye Disease. Pharm. Res. 2019, 36, 36. [Google Scholar] [CrossRef]
  79. Goldberg, D.F.; Malhotra, R.P.; Schechter, B.A.; Justice, A.; Weiss, S.L.; Sheppard, J.D. A Phase 3, Randomized, Double-Masked Study of OTX-101 Ophthalmic Solution 0.09% in the Treatment of Dry Eye Disease. Ophthalmology 2019, 126, 1230–1237. [Google Scholar] [CrossRef] [Green Version]
  80. Li, S.; Lu, Z.; Huang, Y.; Wang, Y.; Jin, Q.; Shentu, X.; Ye, J.; Ji, J.; Yao, K.; Han, H. Anti-Oxidative and Anti-Inflammatory Micelles: Break the Dry Eye Vicious Cycle. Adv. Sci. 2022, 9, e2200435. [Google Scholar] [CrossRef]
  81. García, A.L.M.; Bailey, R.; Jana, S.; Burgess, J.G. The role of polymers in cross-kingdom bioadhesion. Philos. Trans. R. Soc. B Biol. Sci. 2019, 374, 20190192. [Google Scholar] [CrossRef] [Green Version]
  82. Partenhauser, A.; Bernkop-Schnürch, A. Mucoadhesive polymers in the treatment of dry X syndrome. Drug Discov. Today 2016, 21, 1051–1062. [Google Scholar] [CrossRef]
  83. Luo, L.-J.; Lai, J.-Y. Epigallocatechin Gallate-Loaded Gelatin-g-Poly(N-Isopropylacrylamide) as a New Ophthalmic Pharmaceutical Formulation for Topical Use in the Treatment of Dry Eye Syndrome. Sci. Rep. 2017, 7, 9380. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Park, C.G.; Kim, M.J.; Park, M.; Choi, S.Y.; Lee, S.H.; Lee, J.E.; Shin, G.-S.; Park, K.H.; Bin Choy, Y. Nanostructured mucoadhesive microparticles for enhanced preocular retention. Acta Biomater. 2014, 10, 77–86. [Google Scholar] [CrossRef]
  85. Vicario-de-la-Torre, M.; Benítez-del-Castillo, J.; Vico, E.; Guzmán, M.; de-Las-Heras, B.; Herrero-Vanrell, R.; Molina-Martínez, I. Design and characterization of an ocular topical liposomal preparation to replenish the lipids of the tear film. Investig. Ophthalmol. Vis. Sci. 2014, 55, 7839–7847. [Google Scholar] [CrossRef] [Green Version]
  86. Mencucci, R.; Strazzabosco, G.; Cristofori, V.; Alogna, A.; Bortolotti, D.; Gafà, R.; Cennamo, M.; Favuzza, E.; Trapella, C.; Gentili, V.; et al. GlicoPro, Novel Standardized and Sterile Snail Mucus Extract for Multi-Modulative Ocular Formulations: New Perspective in Dry Eye Disease Management. Pharmaceutics 2021, 13, 2139. [Google Scholar] [CrossRef] [PubMed]
  87. Liu, Y.; Wang, Y.; Yang, J.; Zhang, H.; Gan, L. Cationized hyaluronic acid coated spanlastics for cyclosporine A ocular delivery: Prolonged ocular retention, enhanced corneal permeation and improved tear production. Int. J. Pharm. 2019, 565, 133–142. [Google Scholar] [CrossRef]
  88. Ho, T.-C.; Chang, C.-C.; Chan, H.-P.; Chung, T.-W.; Shu, C.-W.; Chuang, K.-P.; Duh, T.-H.; Yang, M.-H.; Tyan, Y.-C. Hydrogels: Properties and Applications in Biomedicine. Molecules 2022, 27, 2902. [Google Scholar] [CrossRef] [PubMed]
  89. Pandey, M.; Choudhury, H.; Aziz, A.B.A.; Bhattamisra, S.; Gorain, B.; Su, J.; Tan, C.; Chin, W.; Yip, K. Potential of Stimuli-Responsive In Situ Gel System for Sustained Ocular Drug Delivery: Recent Progress and Contemporary Research. Polymers 2021, 13, 1340. [Google Scholar] [CrossRef]
  90. Ma, B.; Pang, L.; Huang, P.; Bai, J.; Zhang, Z.; Wu, H.; Cai, M.; Yang, J.; Xu, Y.; Yin, X.; et al. Topical Delivery of Levocarnitine to the Cornea and Anterior Eye by Thermosensitive in-situ Gel for Dry Eye Disease. Drug Des. Dev. Ther. 2021, 15, 2357–2373. [Google Scholar] [CrossRef] [PubMed]
  91. Han, Y.; Jiang, L.; Shi, H.; Xu, C.; Liu, M.; Li, Q.; Zheng, L.; Chi, H.; Wang, M.; Liu, Z.; et al. Effectiveness of an ocular adhesive polyhedral oligomeric silsesquioxane hybrid thermo-responsive FK506 hydrogel in a murine model of dry eye. Bioact. Mater. 2022, 9, 77–91. [Google Scholar] [CrossRef] [PubMed]
  92. Eldesouky, L.; El-Moslemany, R.; Ramadan, A.; Morsi, M.; Khalafallah, N. Cyclosporine Lipid Nanocapsules as Thermoresponsive Gel for Dry Eye Management: Promising Corneal Mucoadhesion, Biodistribution and Preclinical Efficacy in Rabbits. Pharmaceutics 2021, 13, 360. [Google Scholar] [CrossRef] [PubMed]
  93. Choi, J.H.; Li, Y.; Jin, R.; Shrestha, T.; Choi, J.S.; Lee, W.J.; Moon, M.J.; Ju, H.T.; Choi, W.; Yoon, K.C. The Efficiency of Cyclosporine A-Eluting Contact Lenses for the Treatment of Dry Eye. Curr. Eye Res. 2019, 44, 486–496. [Google Scholar] [CrossRef]
  94. Gupta, C.; Chauhan, A. Ophthalmic delivery of cyclosporine A by punctal plugs. J. Control Release 2011, 150, 70–76. [Google Scholar] [CrossRef]
  95. Terreni, E.; Chetoni, P.; Burgalassi, S.; Tampucci, S.; Zucchetti, E.; Chipala, E.; Alany, R.G.; Al-Kinani, A.A.; Monti, D. A hybrid ocular delivery system of cyclosporine-A comprising nanomicelle-laden polymeric inserts with improved efficacy and tolerability. Biomater. Sci. 2021, 9, 8235–8248. [Google Scholar] [CrossRef]
  96. Xie, J.; Wang, C.; Ning, Q.; Gao, Q.; Gao, C.; Gou, Z.; Ye, J. A new strategy to sustained release of ocular drugs by one-step drug-loaded microcapsule manufacturing in hydrogel punctal plugs. Graefe’s Arch. Clin. Exp. Ophthalmol. 2017, 255, 2173–2184. [Google Scholar] [CrossRef] [PubMed]
  97. Navarro-Gil, F.J.; Huete-Toral, F.; Domínguez-Godínez, C.O.; Carracedo, G.; Crooke, A. Contact Lenses Loaded with Melatonin Analogs: A Promising Therapeutic Tool against Dry Eye Disease. J. Clin. Med. 2022, 11, 3483. [Google Scholar] [CrossRef]
  98. Dominguez-Godinez, C.; Carracedo, G.; Pintor, J. Diquafosol Delivery from Silicone Hydrogel Contact Lenses: Improved Effect on Tear Secretion. J. Ocul. Pharmacol. Ther. 2018, 34, 170–176. [Google Scholar] [CrossRef] [PubMed]
  99. Akbari, E.; Imani, R.; Shokrollahi, P.; Keshel, S.H. Preparation of Nanoparticle-Containing Ring-Implanted Poly(Vinyl Alcohol) Contact Lens for Sustained Release of Hyaluronic Acid. Macromol. Biosci. 2021, 21, 2100043. [Google Scholar] [CrossRef] [PubMed]
  100. Tauber, J.; Wirta, D.L.; Sall, K.; Majmudar, P.A.; Willen, D.; Krösser, S.; for the SEECASE Study Group. A Randomized Clinical Study (SEECASE) to Assess Efficacy, Safety, and Tolerability of NOV03 for Treatment of Dry Eye Disease. Cornea 2020, 40, 1132–1140. [Google Scholar] [CrossRef]
  101. Steven, P.; Augustin, A.J.; Geerling, G.; Kaercher, T.; Kretz, F.; Kunert, K.; Menzel-Severing, J.; Schrage, N.; Schrems, W.; Krösser, S.; et al. Semifluorinated Alkane Eye Drops for Treatment of Dry Eye Disease Due to Meibomian Gland Disease. J. Ocul. Pharmacol. Ther. 2017, 33, 678–685. [Google Scholar] [CrossRef]
  102. Schmidl, D.; Bata, A.; Szegedi, S.; Santos, V.A.D.; Stegmann, H.; Fondi, K.; Krösser, S.; Werkmeister, R.; Schmetterer, L.; Garhöfer, G. Influence of Perfluorohexyloctane Eye Drops on Tear Film Thickness in Patients with Mild to Moderate Dry Eye Disease: A Randomized Controlled Clinical Trial. J. Ocul. Pharmacol. Ther. 2020, 36, 154–161. [Google Scholar] [CrossRef] [PubMed]
  103. Sheppard, J.; Wirta, D.; McLaurin, E.; Boehmer, B.; Ciolino, J.; Meides, A.; Schlüter, T.; Ousler, G.; Usner, D.; Krösser, S. A Water-free 0.1% Cyclosporine A Solution for Treatment of Dry Eye Disease: Results of the Randomized Phase 2B/3 ESSENCE Study. Cornea 2021, 40, 1290–1297. [Google Scholar] [CrossRef] [PubMed]
  104. Wirta, D.L.; Torkildsen, G.L.; Moreira, H.R.; Lonsdale, J.D.; Ciolino, J.B.; Jentsch, G.; Beckert, M.; Ousler, G.W.; Steven, P.; Krösser, S. A Clinical Phase II Study to Assess Efficacy, Safety, and Tolerability of Waterfree Cyclosporine Formulation for Treatment of Dry Eye Disease. Ophthalmology 2019, 126, 792–800. [Google Scholar] [CrossRef] [PubMed]
Bioengineering 10 00053 g001 550
Figure 1. Drug delivery systems for DED.
Figure 1. Drug delivery systems for DED.
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Figure 2. Schematic illustration for the preparation of rebamipide ultrafine suspension. Reprinted with permission from [33]. Copyright 2017 The Pharmaceutical Society of Japan.
Figure 2. Schematic illustration for the preparation of rebamipide ultrafine suspension. Reprinted with permission from [33]. Copyright 2017 The Pharmaceutical Society of Japan.
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Figure 3. Schematic illustration for the preparation of adriamycin liposomes. Reprinted with permission from [57]. Copyright 2018 American Chemical Society.
Figure 3. Schematic illustration for the preparation of adriamycin liposomes. Reprinted with permission from [57]. Copyright 2018 American Chemical Society.
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Figure 4. Schematic illustration of the (a) single emulsion method and (b) multiple emulsion method for microsphere preparation. Reprinted from [68] under Creative Commons Attribution License.
Figure 4. Schematic illustration of the (a) single emulsion method and (b) multiple emulsion method for microsphere preparation. Reprinted from [68] under Creative Commons Attribution License.
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Figure 5. Schematic illustration for the preparation (a) and characterization (b–g) of anti-inflammatory and antioxidant micelles. Reprinted from [80] under Creative Commons Attribution License.
Figure 5. Schematic illustration for the preparation (a) and characterization (b–g) of anti-inflammatory and antioxidant micelles. Reprinted from [80] under Creative Commons Attribution License.
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Figure 6. Schematic illustration for the preparation of FK506-encapsulated temperature-sensitive hydrogel. Reprinted from [91] under the CC BY-NC-ND license.
Figure 6. Schematic illustration for the preparation of FK506-encapsulated temperature-sensitive hydrogel. Reprinted from [91] under the CC BY-NC-ND license.
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Figure 7. Schematic illustration for the design of a cyclosporine-releasing punctal plug. Reprinted with permission from [94]. Copyright 2011 Elsevier.
Figure 7. Schematic illustration for the design of a cyclosporine-releasing punctal plug. Reprinted with permission from [94]. Copyright 2011 Elsevier.
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Table
Table 1. Drug delivery systems for DED in the market or under clinical investigation.
Table 1. Drug delivery systems for DED in the market or under clinical investigation.
Commercial ProductMain IngredientDrug Delivery MethodCompanyTime to
Market
Restasis®Cyclosporine A, Polysorbate, Castor Oil, Carbomer, etc.O/W anionic nanoemulsionAllergan, Irvine, CA, USADecember 2002
Cationorm®Mineral Oil, Glycerin, Tyloxapol, Poloxamer 188, etc.O/W cationic nanoemulsionSanten Pharmaceutical, Osaka, Japan May 2008
Tears Again®Soy Lecithin, Sodium Chloride, Vitamin A, Palmitic Acid and Vitamin E, etc.Liposome sprayOptima
Pharmaceutical, Hallbergmoos, Germany		September 2008
Soothe XP®Light Mineral Oil (1.0%), Boric Acid, Mineral Oil (4.5%), etc.O/W anionic nanoemulsionBausch & Lomb, Clearwater, FL, USAMay 2010
Mucosta®Rebamipide, polyvinyl alcohol, sodium citrate hydrate, sodium chloride.SuspensionOtsuka Pharmaceutical, Tokyo, JapanJanuary 2012
Ikervis®Cyclosporine A, Medium Chain Triglycerides, Glycerin, Tyloxapol, etc.O/W cationic nanoemulsionSanten Pharmaceutical, Osaka, Japan March 2015
Cequa®Cyclosporine A, polyoxyethylene hydrogenated castor oil, etc.NanomicelleSun Pharmaceutical, Mumbai, IndiaAugust 2018
EYSUVIS®0.25% Loteprednol Etabonate, etc.NanosuspensionKala Pharmaceuticals, Arlington, MA, USAOctober 2020
Tyrvaya®vareniclinewater-based nasal sprayOyster Point Pharmaceutical, Princeton, NJ, USAOctober 2021
VisuEvo®omega-3s, vitamins A and D, and phospholipids, etc.LiposomesVisufarma SpA, Rome, Italy Clinical Trials
VisuXL®Coenzyme Q10, Vitamin E TPGS and Sodium Carboxymethylcellulose.HydrogelVisufarma SpA, Rome, ItalyClinical Trials
NOV 03®Perfluorohexyloctane Anhydrous Drug Delivery SystemNovaliq, Baden-Wurttemberg, GermanyClinical Trials
CyclASol®0.1% Cyclosporine A, Semifluorinated alkaneAnhydrous Drug Delivery SystemNovaliq, Baden-Wurttemberg, GermanyClinical Trials
Table
Table 2. Bioadhesive polymers for the treatment of DED [82].
Table 2. Bioadhesive polymers for the treatment of DED [82].
ClassificationCompositionProduct
NaturalGuar GumSystane®
Hyaluronic AcidHyloforte®
Hylocomod®
Artelac®
Semi-syntheticCellulose DerivativeLacrisert®
Systane®
Celluvisc®
SyntheticPolyacrylic AcidArtelac®
Vidisic®
PolyvinylpyrrolidoneProtagent®
Lacrisic®
Polyvinyl AlcoholLiquifilm o.k®
Thiolate CompoundsLacrimera®
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Wang, T.-Z.; Liu, X.-X.; Wang, S.-Y.; Liu, Y.; Pan, X.-Y.; Wang, J.-J.; Nan, K.-H. Engineering Advanced Drug Delivery Systems for Dry Eye: A Review. Bioengineering 2023, 10, 53. https://doi.org/10.3390/bioengineering10010053

AMA Style

Wang T-Z, Liu X-X, Wang S-Y, Liu Y, Pan X-Y, Wang J-J, Nan K-H. Engineering Advanced Drug Delivery Systems for Dry Eye: A Review. Bioengineering. 2023; 10(1):53. https://doi.org/10.3390/bioengineering10010053

Chicago/Turabian Style

Wang, Tian-Zuo, Xin-Xin Liu, Si-Yu Wang, Yan Liu, Xin-Yang Pan, Jing-Jie Wang, and Kai-Hui Nan. 2023. "Engineering Advanced Drug Delivery Systems for Dry Eye: A Review" Bioengineering 10, no. 1: 53. https://doi.org/10.3390/bioengineering10010053

APA Style

Wang, T. -Z., Liu, X. -X., Wang, S. -Y., Liu, Y., Pan, X. -Y., Wang, J. -J., & Nan, K. -H. (2023). Engineering Advanced Drug Delivery Systems for Dry Eye: A Review. Bioengineering, 10(1), 53. https://doi.org/10.3390/bioengineering10010053

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