Micelle-Based Ocular Inserts for Sustained Delivery and Improved Corneal Permeation of Rebamipide in Dry Eye Disease

Abstract

Background: Rebamipide (REB) is a poorly water-soluble drug with limited ocular bioavailability, necessitating advanced delivery strategies for sustained therapy in dry eye disease.

Methods: In the present study, micelle-assisted ocular inserts were developed using non-ionic surfactants to enhance REB solubilization, drug loading, and controlled ocular delivery. The intrinsic solubility of REB in simulated tear fluid (STF, pH 7.4) was evaluated and compared with micellar systems. The formulations were characterized for particle size, polydispersity index, and zeta potential. Ocular inserts were fabricated via UV photopolymerization and evaluated for physicochemical properties, drug content, in vitro drug release, ex vivo permeation, cytocompatibility using SIRC cells, and histopathological analysis.

Results: REB exhibited low intrinsic solubility in STF (26.05 ± 1.00 µg/mL), which was significantly enhanced in micellar systems, particularly with Solutol HS 15 (306.71 ± 1.10 µg/mL) and Tween 80 (263.18 ± 1.19 µg/mL). All micellar formulations formed stable nanosized micelles (7.5–15.1 nm) with low polydispersity (PDI < 0.35) and near-neutral zeta potential (−0.08 to −2.81 mV). The prepared ocular inserts showed uniform thickness, weight, and physiological surface pH. Micelle-assisted inserts demonstrated significantly higher drug content (87.40 ± 3.25 to 99.19 ± 2.44 µg/insert) compared to plain REB inserts (21.41 ± 2.28 µg/insert). In- vitro studies revealed sustained drug release over 24 h (92.25 ± 1.64 to 100.50 ± 1.10%), whereas plain inserts showed burst release. Ex vivo permeation studies indicated enhanced drug permeation (up to 77.30 ± 0.34 µg) and improved flux (1.38–8.52 µg/cm²·h) compared to plain REB. Cytocompatibility studies confirmed >90% SIRC cell viability, and histopathological analysis showed no structural damage to corneal tissue.

Conclusions: Micelle-assisted ocular inserts, particularly those formulated with Solutol HS 15 and Tween 80, provide a promising platform for sustained, safe, and effective ocular delivery of Rebamipide in the management of dry eye disease.

Introduction

Dry eye disease (DED) is a multifactorial ocular surface disorder resulting from an imbalance in tear film homeostasis caused by inadequate tear production or excessive tear evaporation [1]. This disruption alters the delicate equilibrium among tear secretion, distribution, and drainage, leading to ocular surface damage and patient discomfort. The tear film plays a crucial role in providing lubrication, antimicrobial defense, and corneal healing support. Hence, its dysfunction compromises both ocular health and visual quality. Globally, DED affects approximately 5–30% of the population, with prevalence increasing markedly with age [2,3,4].

Pathophysiologically, DED is primarily associated with the dysfunction of the lacrimal functional unit, which includes the lacrimal glands, ocular surface, and their neural connections. A deficiency of anti-inflammatory tear components leads to the activation of T-lymphocytes, which subsequently release pro-inflammatory cytokines that induce inflammation and epithelial damage to the ocular surface [2,5,6,7]. Clinically, DED manifests through a wide spectrum of symptoms such as ocular pain, redness, burning sensation, excessive tearing, foreign body sensation, and fluctuating vision. These symptoms not only cause physical discomfort but also significantly reduce quality of life, impairing daily activities like reading, driving, and extended screen use. Such widespread impact emphasizes the necessity of developing effective, patient-compliant therapeutic options for managing DED [8,9,10,11].

The goals of DED treatment are to restore the ocular surface and normalize tear film production, improve patient comfort, and alleviate symptoms, with current therapeutic approaches ranging from artificial tear formulations, anti-inflammatory agents, mucin secretagogues, corticosteroids, dietary supplements such as omega-3 fatty acids, vitamin A, autologous serum eye drops, antibiotics including tetracyclines and macrolides, immunomodulators such as tacrolimus, punctal plugs, and surgical interventions [12,13]. Among these options, rebamipide (REB) offers a unique therapeutic advantage by directly addressing mucin deficiency, a key pathological factor in DED, thereby restoring tear film stability and promoting ocular surface healing rather than providing only symptomatic relief [14,15]. REB, a quinolinone derivative, was originally developed as a mucosal protective agent for treating gastric ulcers and chronic gastritis due to its potent mucin-enhancing and anti-inflammatory properties [16]. It stimulates mucin secretion in gastric epithelial cells, scavenges reactive oxygen species, and suppresses inflammatory cytokine production, thereby supporting mucosal healing and barrier integrity [17]. Beyond gastrointestinal applications, REB has gained considerable attention in ophthalmology, particularly for DED management, where it functions as a mucin secretagogue that restores tear film stability and promotes epithelial healing. Clinical and preclinical studies have demonstrated that REB increases the number of conjunctival goblet cells and promotes secretion of mucin-like glycoproteins in both corneal and conjunctival epithelia, improving lubrication and overall ocular surface integrity [2,5].

The ophthalmic suspension of REB, commercially available as Mucosta® Ophthalmic Suspension UD 2% by Otsuka Pharmaceutical Co. (Japan), was approved in 2011 following successful clinical trials. Patients treated with four daily doses of this formulation showed significant improvements in tear film breakup time, vital staining scores, and overall ocular comfort, confirming REB’s therapeutic efficacy in DED [5]. Mechanistic studies have revealed that REB upregulates the expression of membrane-associated mucins such as MUC1, MUC4, and MUC16 through activation of the epidermal growth factor receptor signaling pathway, thereby enhancing epithelial barrier protection and maintaining ocular hydration [18]. Additionally, REB suppresses T-cell activation and cytokine release, contributing to reduced ocular inflammation and accelerated corneal wound healing.

Despite its therapeutic advantages, several formulation-related challenges restrict the clinical efficacy of REB. The drug is practically insoluble in water and exhibits very low solubility in pH-neutral buffer systems appropriate for ocular use, leading to poor bioavailability [19]. The marketed suspension (Mucosta® 2%) is a milky, turbid formulation requiring vigorous shaking before use to re-disperse settled particles. This opacity can cause transient blurred vision and ocular irritation due to its high drug concentration (20 mg/mL), which negatively impacts patient compliance [16]. Furthermore, REB is categorized as a Biopharmaceutical Classification System (BCS) Class IV drug, characterized by both low solubility and low permeability, with logP and pKa values of 2.9 and 3.3, respectively. Consequently, only a limited fraction of the topically administered dose remains on the ocular surface before being eliminated through tear turnover and nasolacrimal drainage, necessitating frequent dosing to maintain therapeutic levels [20]. Additionally, manufacturing sterile ophthalmic suspensions of REB poses technical challenges, as standard 0.2 µm filtration methods cannot be used for sterilization, complicating large-scale production and increasing manufacturing costs [19]. These limitations collectively underscore the need for advanced delivery systems capable of improving REB solubility, stability, bioavailability, and patient adherence.

Recent research has focused on innovative drug delivery strategies to overcome the inherent limitations of REB. Liposomal REB formulations have demonstrated improved ocular retention, reduced irritation, and sustained release, offering superior therapeutic performance compared to conventional suspensions [16]. Similarly, nanoparticle-based sustained-release systems, developed using bead milling with 2-hydroxypropyl-β-cyclodextrin and methylcellulose, achieved particle sizes between 40 and 200 nm and showed enhanced corneal penetration, sustained mucin secretion, and tear film stabilization in rabbit models [20]. Another approach involved developing clear, supersaturated aqueous eye drops using pH modification and hydrophilic polymers such as hydroxypropyl methylcellulose (4.5 cp). These optimized formulations demonstrated improved solubility, stability, and bioavailability, while minimizing dosing frequency and visual disturbance [19]. Moreover, cationic β-cyclodextrin copolymers significantly enhanced REB solubility and corneal retention without inducing toxicity, improving mucin secretion and overall therapeutic efficacy in experimental DED models [21]. Collectively, these findings highlight the promising evolution of REB delivery platforms liposomes, nanoparticles, supersaturated solutions, and β-cyclodextrin complexes that enhance its ocular bioavailability and patient comfort.
Nevertheless, these systems still face limitations in achieving long-term retention and controlled release on the ocular surface. REB’s poor aqueous solubility and rapid precorneal elimination continue to hinder sustained therapeutic exposure [22]. To address these shortcomings, micellar systems have emerged as an effective nanocarrier platform for ocular drug delivery. Micelles are self-assembled colloidal structures formed by amphiphilic polymers above their critical micelle concentration (CMC). They consist of a hydrophobic core that solubilizes poorly water-soluble drugs and a hydrophilic shell that stabilizes the system in an aqueous environment. Incorporating REB into polymeric micelles not only enhances its solubility and stability but also facilitates trans-corneal permeation and cellular uptake. Building on this concept, the present research utilizes a micellar–ocular insert hybrid system for the delivery of REB. In this approach, a micellar solution containing solubilized REB is used to impregnate pre-formed polymeric ocular inserts, enabling efficient drug loading through diffusion and adsorption within the polymeric matrix. Upon administration, these micelle-laden inserts provide sustained drug release and enhanced residence time compared to conventional eye drops. Unlike plain REB solution, which is rapidly cleared from the ocular surface, the insert ensures continuous and localized delivery, thereby improving therapeutic efficacy and patient compliance [23,24]. Such a combination strategy integrates the solubilization advantage of micelles with the prolonged retention properties of ocular inserts, creating a synergistic platform that can overcome multiple formulation challenges simultaneously. The micellar ocular insert is therefore proposed as a novel, patient-friendly, and efficient delivery system for enhanced management of dry eye disease [25,26].

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Materials

Rebamipide (REB; Mw: 370.35 g·mol−1, purity ≥ 98%) was provided as a gift sample by Dr. Reddy’s Laboratories Ltd., Hyderabad, India. Pluronic® F68 (Poloxamer 188; average Mw ~8400 g·mol−1) and Pluronic® F127 (Poloxamer 407; average Mw ~12,600 g·mol−1) were purchased from Sigma-Aldrich Chemicals Pvt. Ltd., Bangalore, India. Polysorbate 20 (Tween® 20; average Mw ~1227 g·mol−1) and polysorbate 80 (Tween® 80; average Mw ~1310 g·mol−1) were obtained from Merck Life Science Pvt. Ltd., Mumbai, India. Caprylocaproyl polyoxyl-8 glycerides (Labrasol®; average Mw ~365 g·mol−1) and polyoxyethylene esters of 12-hydroxystearic acid (Solutol® HS 15; average Mw ~963 g·mol−1) were procured from Gattefossé India Pvt. Ltd., Mumbai, India. Sodium chloride (NaCl; Mw: 58.44 g·mol−1), potassium chloride (KCl; Mw: 74.55 g·mol−1), sodium bicarbonate (NaHCO3; Mw: 84.01 g·mol−1), and calcium chloride dihydrate (CaCl2·2H2O; Mw: 147.02 g·mol−1) were obtained from Finar Chemicals Ltd., Ahmedabad, India. Fluid thioglycollate medium and soybean–casein digest medium were purchased from HiMedia Laboratories Pvt. Ltd., Mumbai, India. All chemicals and excipients used were of pharmaceutical or analytical grade. Ultrapure water was used throughout the experimental work.

Patel, Y.; Ranch, K.M.; Prajapati, A.; Jani, H.; Ontong, J.C.; Singh, S. Micelle-Based Ocular Inserts for Sustained Delivery and Improved Corneal Permeation of Rebamipide in Dry Eye Disease. Pharmaceutics 2026, 18, 578. https://doi.org/10.3390/pharmaceutics18050578

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