Advanced Drug Delivery for Treating Sjögren’s Dry Eye: History
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Contributor:
Kevin Yang Wu
,
Y-Kim Chu-Bédard
,
Andrew Farag
,
Simon Tran
,

Sjögren’s syndrome is a chronic and insidious autoimmune disease characterized by lymphocyte infiltration of exocrine glands. Patients typically present with dry eye (keratoconjunctivitis sicca), dry mouth (xerostomia), and other systemic manifestations. The current management for Sjögren's syndrome dry eye (SSDE) has been ineffective as it only targets ocular surface inflammation and dryness without addressing the specific disease process. Ophthalmologists often adopt a trial-and-error approach, which allows the cycle of dry eye disease (DED) to progress and potentially cause permanent damage to the lacrimal functional unit. Topical treatments also depend on patients' ability to administer eye drops and their compliance. These limitations emphasize the need for personalized, targeted treatments that address the underlying pathophysiology of SSDE. This article aims to present new advances in ocular drug delivery for more effective treatment.

  • sjögren syndrome
  • dry eye
  • ocular drug delivery
  • topical administration
  • nanocarriers
  • subconjunctival
  • episcleral and intravitreal implant
  • controlled release systems
  • basic research
  • pathophysiology

1. Introduction

Despite recent advancements in clinical pharmacology and extensive efforts to improve ocular manifestations in Sjogren's syndrome (SS) patients, treating SS-related dry eye (SSDE) remains a challenge for ophthalmologists. Our literature review uncovered several promising novel treatment approaches on the horizon, including the use of advanced drug-delivery systems to enhance the efficacy and tolerability of current therapies, as well as targeting the autoimmune pathways and pathogenesis of SSDE. Table 1 highlights the mechanisms and treatment consideration of each therapeutic option discussed.

2. Immunomodulators

The current treatments for Sjögren's Syndrome-associated Dry Eye (SSDE) only manage ocular surface inflammation and dryness. To target the underlying pathogenesis and autoimmunity of Sjögren's syndrome, systemic immunomodulators and disease modifying treatments are being studied. B-cell targeted therapies have been the most researched, including rituximab, a monoclonal antibody targeting CD20 antigen. However, results of studies on the efficacy of rituximab are inconsistent and its use is controversial. Belimumab, a B-cell activating factor (BAFF) inhibitor, has shown potential in improving disease markers and dryness symptoms, but the evidence is weak. Epratuzumab targets CD22 and showed positive results in a study of 16 patients in 2006, but no studies have been conducted since that time.

Recent studies have shown potential benefits in other treatments for SSDE. Ianalumab, another BAFF receptor inhibitor, has shown reduced disease activity. Iguratimod, a macrophage migration inhibitory factor (MIF), has shown improvement in symptoms and inflammatory markers. Abatacept, a T-cell co-stimulation modulator, has shown impact on SS related biomarkers, but results have been inconsistent.

Anti-inflammatory agents, such as infliximab, etanercept, and anakinra, and JAK-1 inhibitor filgotinib have been studied for SS, but with no impact on the disease. RSLV-132, an RNAse fusion protein aimed to reduce IFN activity, showed improvement in severe fatigue in SS patients, but also upregulated IFN-inducible genes.

There are many ongoing clinical trials for treatments of SSDE, but further studies are needed to determine the safety and efficacy of these treatments.

3. Anterior Segment Ocular Drug-Delivery Technologies

3.1. TOP1360

TOP1360, a non-systemic kinase inhibitor, is currently being studied in phase 2 clinical trials for the treatment of dry eye disease (DED). The potential use of non-systemic kinase inhibitors in DED is based on recent research indicating their ability to reduce inflammation in diseases such as ulcerative colitis, chronic obstructive pulmonary disease, and arthritis. These agents target kinases involved in innate and adaptive immune signaling, including p38-alpha, Syk, Srx, and Lck, which have been shown to be upregulated in DED (Taylor et al., 69). A study by Taylor et al. evaluated the effects of TOP1360 0.1% ophthalmic solution in 61 adults with a reported history of DED in both eyes for at least 6 months. The results showed that TOP1360 was safe and well-tolerated, and while the primary endpoint was not a direct evaluation of its efficacy in treating DED, patients receiving TOP1360 reported significant improvement in ocular dryness, discomfort, and grittiness by day 15 of treatment [1].

3.2. Lacritin

Lacritin is a tear glycoprotein that promotes tearing and maintains ocular surface integrity by targeting SDC1 on corneal and conjunctival epithelia via heparinase cleavage, which triggers a signal cascade promoting secretion and proliferation. Vijmasi et al. found that lacritin active fragments were significantly lower in tears of 15 Sjögren's Syndrome (SS) patients compared to 14 healthy controls [2]. Lacritin also showed a 32% increase in tearing within 1 week of treatment (p ˂ 0.001) and a 46% increase by week 3 (p = 0.01). Corneal epithelial damage was significantly reduced. While lacrimal gland lymphocytic infiltration remained similar, the number of lymphocyte foci per millimeter square of gland tissue decreased significantly. This reduction in lymphocyte foci expansion, a sign of autoimmune disease, suggests that lacritin could modulate lacrimal gland inflammation by protecting against lymphocyte infiltration.

3.3. RGN-259

RGN-259 ophthalmic solution, a synthetic of the naturally occurring protein thymosin β4 (found in almost all cells and promotes wound repair in multiple tissues), has been studied for the treatment of neurotrophic keratitis unresponsive to anti-inflammatory agents. Studies showed that it promotes ocular surface healing, increases corneal epithelial cell migration, and reduces corneal pro-inflammatory cytokines. The safety and efficacy of 0.1% Thymosine β4 administered twice daily was established in phase II clinical trials [3]. Mouse studies have also shown positive results, including increased tear production, mucin, and goblet cell density, as well as decreased anti-inflammatory factors, at least as well as diquafosol, cyclosporine A, and lifitegrast [4]. Two phase III clinical trials (ARISE-2 and ARISE-3) were conducted, with ARISE-3 finding clinically significant improvement after one and two weeks of treatment. An additional clinical trial (ARISE-4) is planned for 2024. The safety profile of RGN-259 was found to be excellent [3].

3.4. Contact Lens Drug-Delivery

Contact lenses are an attractive platform for drug delivery due to their ability to control drug release kinetics and their physical barrier properties. They offer increased drug contact time and proximity to the cornea, resulting in enhanced bioavailability compared to other non-invasive formulations [5]. Various drug loading techniques have been developed to accommodate both hydrophobic and hydrophilic molecules. Simple soaking, in which the lens is submerged in a drug-containing solution, is a straightforward technique, but drug uptake and release are limited by lens factors and drug properties. To enhance drug uptake and extend release time, vitamin E-coated lenses can be used in conjunction with soaking. The addition of vitamin E creates a diffusion barrier for the drug. To better accommodate hydrophobic drugs, surfactants can be added to contact lenses, promoting the formation of micelles and preferential partitioning of hydrophobic molecules, such as cyclosporine A. The use of colloidal particles containing active ingredients has also been studied and was found to be successful in sustaining dexamethasone delivery. The latest drug-loading technique is molecular imprinting, in which a molecular meshwork is created to fit a specific molecule. This technique has been applied to diclofenac, resulting in sustained release of therapeutic doses. Evaluations of drug delivery using existing commercial lens materials have been performed with selected pharmaceutical products and have demonstrated efficacy in treating dry eyes.

Contact Lens Drug-Delivery—Anti-Inflammatory

Cyclosporine A is a topical formulation approved by the FDA for the treatment of dry eyes. According to a study by Peng et al., loading cyclosporine A on a silicone hydrogel lens resulted in a delivery rate of 15 days, which was increased to 20 days with the addition of surfactant molecules to the lens mixture [6]. Another study by Boone et al. found that dexamethasone-loading onto silicone hydrogel lenses did not provide an adequate drug release time. However, incorporating surfactants, vitamin E soaking, adjusting monomer ratios, and utilizing drug-loaded colloidal particles showed improved drug release times of up to 3 months [7]. Diclofenac can also be successfully loaded onto contact lenses using methods such as monomer addition and molecular imprinting techniques, allowing for sustained in vitro release of up to 2 weeks. In fact, molecular imprinted contact lenses showed a release of diclofenac comparable to the maximum dose delivered by commercial eye drops [8].

Contact Lens Drug-Delivery—Secretagogue

Secretagogues are compounds that stimulate the secretion of tear fluid and mucins, and they exist in three families: dinucleotides, cholinergic agonists, and mucin secretagogue. While secretagogues have been used effectively as eye drops for the treatment of dry eyes, contact lens drug delivery has only been investigated with dinucleotides. In rabbit eyes, studies have shown that diadenosine tetraphosphate delivered via contact lens resulted in tear secretion above baseline for up to 360 minutes [8].

Contact Lens Drug-Delivery—Osmoprotectant

Osmolarity is a crucial factor in the development of dry eyes. Osmoprotectants, which protect against changes in osmolarity, have been investigated for their potential in treating dry eyes, and current evidence suggests that osmoprotectant solutions may be beneficial. Contact lenses have been explored as a delivery system for these compounds, resulting in drug release times of up to 10 hours. However, further clinical studies are needed to assess the impact of extended release osmoprotectants on dry eyes [8].

Contact Lens Drug-Delivery—Rewetting and Comfort Agents

Rewetting and comfort agents are widely used to alleviate symptoms of dry eyes and include acrylic and polysaccharide-based agents. One such agent, hydroxypropyl methylcellulose, has been shown to improve corneal staining score and break-up time in patients with SSDE. Contact-lens delivery of hydroxypropyl methylcellulose has shown promising results, with imprinted contact lenses resulting in a 6-fold increase in delivery rate compared to eye drop formulations. Despite the promising results, further research is needed to establish the safety and efficacy of contact lens delivery compared to conventional eye drops. Additionally, some of the new materials used for drug loading onto contact lenses require further testing before they can be widely adopted for contact lens production [8].

3.5. Subconjunctival and Episcleral Implants

Subconjunctival and episcleral implants offer many advantages, such as providing sustained drug delivery locally and improved patient compliance. Examples of existing implants are Surodex containing dexamethasone for post-cataract surgery inflammation and LX201 containing cyclosporine A, which is in phase III trials for prevention of corneal graft rejection [5]. Evidence suggests that cyclosporine A subconjunctival implants may be beneficial for treating KCS. Studies on dogs and mares have indicated promising results: Barachetti et al. used 30% cyclosporine implants in 15 dogs with KCS, which were tolerated well and led to a significant reduction in conjunctival hyperemia, corneal neovascularization, corneal opacity, and ocular discharge [9]. Additionally, Mackenzie et al. treated an 8-year-old mare with a 1-month history of KCS using a cyclosporine implant and topical cyclosporine, resulting in improved tear-production and the absence of clinical signs 9 days post-op [10]. These findings suggest that subconjunctival and episcleral implants could provide future opportunities for managing KCS.

3.6. Ocular Iontophoresis

Ocular iontophoresis is a drug delivery technique which uses mild electric charges to cross into anterior and posterior segments. Compared to topical eye drops, it provides higher bioavailability and reduced clearance of active ingredients and offers better compliance than ocular injections. In treating dry eyes, studies have explored the use of iodine and dexamethasone via iontophoresis. In a prospective study of 28 patients, those who received iodine iontophoresis maintained significant objective and subjective improvement at 3 months, while the control group only had subjective improvement at 1 month with no significant improvement at 3 months [11]. Additionally, in a single-center, double-masked, randomized, placebo-controlled phase II trial of 102 patients with confirmed signs and symptoms of dry eyes, those in the lower dose iontophoresis group showed significant improvement in symptoms compared to those in the placebo group [12]. While ocular iontophoresis has demonstrated promising results in improving symptoms of dry eyes, further studies are needed to ascertain specific dosages and applicability to other active compounds.

3.7. Colloidal Nanocarriers for Anterior Segment Disorders

Colloidal nanocarriers are a product of new developments in nanotechnology which could allow for improved pharmacokinetics of existing ocular drugs by their ability to shield drugs from enzymatic destruction and allow passage through ocular barriers, consequently increasing bioavailability. Several nanocarrier subtypes exist.

Colloidal Nanocarriers for Anterior Segment Disorders—Nanomicelles

Nanomicelles, amphiphilic surfactants that can contain hydrophobic drugs such as cyclosporine A, can be used intopical eye drop formulations. Recently, the FDA approved Cequa, a nanomicellar topical formulation of cyclosporine, which has been shown to improve signs and symptoms of dry eyes safely and effectively [13]. Its pharmacokineticadvantages are improved residence time in ocular tissues and higher concentration in ocular tissues compared to theoriginal formulation (Restasis). Pharmacokinetic studies reported that concentrations of cyclosporine delivered bynanomicelle were 3.6 and 3.44-fold higher in conjunctival and scleral tissues, respectively, than with Restasis [13]. Currently, nanomicelles are being studied for delivering nucleic acids, including miRNA.

Colloidal Nanocarriers for Anterior Segment Disorders—Nanoparticles

Nanoparticles are 50–500 nm nanocarriers which have been studied to carry lipophilic drugs, hydrophilic drugs, polynucleotides, and even gene therapy. Research on nanoparticles loaded with active pharmaceutical products studied in the treatment of SS dry eyes have been conducted. De Campos et al. evaluated chitosan nanoparticles as a possible vehicle for cyclosporine A delivery to the ocular surface in rabbits. This study found that therapeutic concentration was achieved for at least 48 h in targeted corneal and conjunctival tissues without significant systemic levels [14].

Colloidal Nanocarriers for Anterior Segment Disorders—Liposomes

Liposomes, colloidal nanocarriers that can encapsulate both hydrophilic and hydrophobic compounds, have been studied for the treatment of dry eyes in rats using azithromycin. This showed higher efficacy in reducing symptomsthan hyaluronic acid drops. While topical liposomes have been studied with other ocular drugs, further research isneeded to investigate their application to SSDE treatments [15].

Colloidal Nanocarriers for Anterior Segment Disorders—Dendrimers

Dendrimers provide the advantage of customizability, as their shape, size, and surface functional groups can beadjusted to accommodate different drug molecules and target tissues. While no research has been done on theirapplication to dry-eye treatments, active products such as dexamethasone have been successfully cross-linked to dendrimers and studied in rat models for treatment of corneal inflammation, diabetic retinopathy (DR), and age-related macular degeneration (AMD). These studies reported enhanced ocular permeability compared to eye drop formulations [16][17].

Colloidal Nanocarriers for Anterior Segment Disorders—Microneedles

Microneedles are an existing drug delivery vehicle which is used for transdermal drug delivery. It is a minimally invasive technique in which microneedles coated with either hydrophilic or hydrophobic drugs are applied to anterior or posterior ocular segments. This formulation has been shown to penetrate the corneal layer and allow for localized drug delivery. Further studies need to be done to evaluate their potential clinical use [18].

Colloidal Nanocarriers for Anterior Segment Disorders—Nanowafers

Nanowafers, small disc formulations intended to be smeared on the ocular surface, are designed for continuous release of drugs from the anterior ocular surface, thus increasing residence time and bioavailability and acting as a protectivelayer for the corneal surface. When used with dexamethasone in the control of inflammation in mice dry eyes, 24 h ofsustained release of dexamethasone was reported following an initial burst in the first hour, and the nanowafers werefound to have equivalent efficacy to the drops in reducing expression of inflammation markers on the cornea [15]. Research into colloidal nanocarriers has yielded promising results which could be applied to the treatment of SSDE.Their ability to provide sustained and localized drug delivery systems could be beneficial for drug bioavailability, efficacy, and safety.

4. Posterior Segment Ocular Drug-Delivery Technologies

Intravitreal Implants

Intravitreal implants are drug eluting devices inserted in the vitreous humor that can be used for prolonged drug release in the treatment of a variety of ocular disorders, such as diabetic retinopathy (DR), diabetic macular edema (DME), age-related macular degeneration (AMD), central retinal vein occlusion (CRVO), and posterior uveitis. Implants that have received FDA approval include Durasert technology system, NOVADUR and Ivation TA [5]. Although these implants have yet to be tested in the treatment of dry eye syndrome, their use in other disorders may suggest potential utility. For instance, the Durasert formulation includes implants loaded with ganciclovir for the treatment of cytomegalovirus retinitis and with fluocinolone acetonide for the treatment of posterior uveitis and diabetic macular edema [19]. Additionally, the Durasert fluocinolone loaded insert Iluvien is currently being studied for its efficacy in AMD and macular edema due to retinal vein occlusion in comparison to Lucentis [5]. Some evidence exists that fluocinolone acetonide implants may be beneficial.

Table 1. Summary of emerging treatment options for SSDE.
Clinical Trials
Biologic Immunomodulators Immunomodulation through innate and adaptive immune system.
Rituxumab: anti-CD20 antibody [20]
Belimumab: anti-BAFF antibody [21]
Epratuzumab: anti-CD20 antibody [22]
Ianalumab: anti-BAFF receptor antibody [23]
Iguratimod: MIF inhibitor [24][25]
Abatacept: CD80/86:CD28 costimulation
inhibitor [26][27]		 Limited studies on efficacy and safety with often conflicting results [20][21][22][23][24][25][26][27].
RSLV-132 RNAse targeting IFN [28] Improved severe fatigue in Sjogren’s [28].
Non-serious side effects like fatigue and infections [28].
RGN-259 Anti-inflammatory, anti-apoptotic, and wound healing properties through thymosine β4 activity [3] Reported excellent safety profile [3][4] Pending additional dry eye trial (ARISE-4) in 2023 [4].
Mesenchymal Stem Cells and Exosomes Immunomodulation, regeneration May restore gland function.
Exosomes are more accessible.
Stem cells limited by donor compatibility and preparation.
Dexamethasone Subconjonctival Implant (Surodex) Immunosuppression through NF-κB suppression and phospholipase A inhibition [5] Sustained drug delivery locally
Better patient compliance
Currently undergoing phase III studies for prevention of corneal graft rejection.
Cyclosporine A Subconjunctival Implants Immunomodulation and anti-inflammation via calcineurin inhibition [9][10] Studies showing encouraging results in animals [9][10]
Iodide Iontophoresis Use of mild electric charges applied to drug molecules allowing for passage into anterior and posterior segments [11][12] Higher bioavailability
Reduced clearance of active ingredients
Better compliance than ocular injection
Further studies needed to determine specific dosage and applicability to other active pharmaceutical compounds
Dexamethasone Iontophoresis
Chitosan Nanoparticles Containing Cyclosporine A Immunomodulation and anti-inflammation via calcineurin inhibition [14] Sustained therapeutic drug concentrations in corneal and conjunctival tissues
Azithromycin Liposomes Immunomodulatory and anti-inflammatory effects through decreased NF-κB, IL-6, IL-8, and MMP-2 activity, and increased TGF-β1 Reduced symptoms of dry eyes in rats
Studies remain to be done in SS
Dendrimer Drug-Delivery Nanocarriers that can be customized to accommodate different drug molecules [16][17] No research has been done applying to dry-eye treatment
Successful cross-linkage of active products used in dry-eye treatment
Nanowafers Nanodisc formulation intended to be smeared on ocular surface with fingertips [5][15] Continuous drug release to anterior ocular surface
Improved residence time and bioavailability
Studied to reduce inflammation markers of cornea in mice.
Fluocinolone Acetonide Intravitreal Implant Drug-eluting device inserted into vitreous humor [29] Prolonged drug release
Existing technology having received FDA approval.
One case report of use for treatment of SS
Not utilized
Immunomodulators Infliximab: TNF-a inhibitor [30]
Etanercept: TNF-a inhibitor [30]
Anakinra: IL-1 antagonist [31]
Tocilizumab: IL-6 receptor agonist [32]
Filgotinib: JAK-1 inhibitor [33]
Ianraplenib: STK inhibitor [33]
Tirabrutinib: BTK inhibitor [33]
Baminercept: Lymphotoxin-b receptor fusion protein inhibitor [34]		 Found ineffective in Sjogren’s disease [30][31][32][33][34]
Microneedle Drug-Delivery Application of microneedle coated with active ingredients to anterior or posterior ocular segments [18] Further studies needed to establish potential clinical use

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15010147

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