Emulgel For Keratoconjunctivitis Sicca

Abstract

Commonly referred to as dry eye disease, keratoconjunctivitis sicca (KCS) is a chronic disorder marked by irritation, inflammation of the ocular surface, and instability of the tear film. Artificial tears, anti-inflammatory drugs, and punctal plugs are examples of current therapeutic methods; however, these sometimes only offer short-term respite and necessitate repeated administration. Emulgels, a hybrid formulation that combines the advantages of gels and emulsions, have become a viable substitute for long-term medication administration in ocular applications. This study investigates emugel's potential as a successful treatment for KCS, emphasizing how it can increase patient compliance, prolong ocular surface residence duration, and improve medication retention. Bioadhesive polymers are used in the formulation to improve mucoadhesion, which guarantees longer hydration and fewer doses. Furthermore, the emulsion-based approach makes it possible to effectively encapsulate and regulate the release of active ingredients, including corticosteroids, cyclosporine, or hyaluronic acid, to reduce inflammation and stabilize tear films. In comparison to traditional eye drops, preliminary in vitro and in vivo tests show better absorption, increased corneal penetration, and improved tear film stability. Emugels' rheological characteristics make application simple while halting the ocular surface's fast draining. Emugels may transform dry eye treatment, according to promising results from clinical trials evaluating efficacy, tolerability, and safety. To sum up, emugels offer a novel, patient-friendly, and effective approach to managing KCS that may enhance long-term ocular health and treatment compliance. Their broad use in ophthalmology may be made possible by additional study and advancement.

Keywords

Introduction

Keratoconjunctivitis Sicca (KCS), commonly known as Dry Eye Disease (DED), is a prevalent ocular condition resulting from insufficient or poor-quality tear production, leading to discomfort, visual disturbances, and, in severe cases, corneal damage. The condition is particularly common in older adults, postmenopausal women, and individuals with autoimmune diseases such as Sjögren’s syndrome [1,2]. Additionally, factors like prolonged screen exposure, environmental pollution, and extensive contact lens use contribute to the rising prevalence of KCS, making it a growing public health concern [3,4]. The tear film plays a crucial role in ocular surface maintenance, comprising a lipid layer that prevents excessive evaporation, an aqueous layer providing hydration and nourishment, and a mucin layer that stabilizes and distributes tears evenly. Any disruption in this balance can result in rapid tear evaporation, ocular surface inflammation, and epithelial damage, leading to persistent symptoms of dry eye [5,6]. Although various treatment options exist for KCS, including artificial tears, ophthalmic gels, anti-inflammatory eye drops, and surgical interventions, their effectiveness is often compromised by poor ocular retention, rapid drug clearance, and the necessity for frequent administration, which reduces patient compliance [7,8]. In response to these limitations, emulgels have emerged as an advanced drug delivery system combining the advantages of emulsions and gels. Emulgels improve drug bioavailability by enhancing retention time on the ocular surface, facilitating better corneal penetration, and ensuring controlled drug release, thereby reducing the need for frequent dosing [9,10]. Additionally, their bioadhesive nature prolongs drug contact with the ocular surface, while their biphasic nature enables the delivery of both hydrophilic and lipophilic drugs [11,12]. Given these benefits, emulgels represent a promising and patient-friendly alternative to conventional KCS therapies. This review explores the formulation, mechanism of action, clinical advancements, and future prospects of emulgels in ophthalmic drug delivery [13,14].

Pathophysiology of Keratoconjunctivitis

Keratoconjunctivitis Sicca (KCS), widely known as dry eye disease, is a complex, multifactorial condition marked by disruption of the tear film and a corresponding cascade of ocular symptoms, including irritation, redness, and visual disturbances [1]. The tear film plays a critical role in maintaining ocular surface health, composed of a structured lipid layer (secreted by meibomian glands), an aqueous layer (produced by lacrimal glands), and a mucin layer (originating from conjunctival goblet cells) [2]. Dysfunction in any of these components — whether through insufficient aqueous secretion in diseases like Sjögren’s syndrome or excessive evaporation due to meibomian gland dysfunction — leads to tear film instability and hyperosmolarity [3]. Tear hyperosmolarity acts as a central pathogenic driver, damaging epithelial cells and triggering inflammatory responses involving cytokines such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), and matrix metalloproteinases (MMPs), ultimately leading to further epithelial injury and goblet cell loss [4]. Persistent hyperosmolar stress initiates a vicious cycle of inflammation, tear film destabilization, and ocular surface damage, with sensory nerve impairment compounding the disease progression [5]. Environmental factors like dry climates, prolonged visual tasks, and certain systemic medications can exacerbate this cycle, resulting in chronic ocular surface disease and significantly impacting patient quality of life [6]. Addressing the underlying mechanisms — particularly tear film instability and inflammation — is vital for effective treatment. Innovative drug delivery systems, notably emulgel formulations, show promise by enhancing ocular drug retention, delivering anti-inflammatory therapies more efficiently, and improving patient adherence [7]. Such targeted approaches aim to interrupt the pathological cycle of KCS and promote long-term ocular surface restoration.

Current treatment strategies for Keratoconjunctivitis Sicca

Managing keratoconjunctivitis sicca (KCS), commonly referred to as dry eye disease, remains a significant therapeutic challenge due to its multifactorial pathogenesis. Current treatments focus on restoring tear film stability, mitigating ocular surface inflammation, and enhancing patients' overall quality of life. Management is typically individualized based on disease severity and underlying causes [1]. Early interventions emphasize patient education and environmental modifications, such as limiting screen exposure, maintaining optimal humidity, and minimizing exposure to air drafts. Artificial tears, particularly preservative-free formulations, serve as the initial mainstay for symptom relief, although they primarily address lubrication rather than underlying inflammation [2]. As the disease progresses, anti-inflammatory therapies become crucial. Topical corticosteroids are often prescribed for short-term control of acute exacerbations, while immunomodulatory agents like cyclosporine A and lifitegrast are preferred for long-term disease modulation by suppressing T-cell activity and inflammatory cytokines [3,4]. In cases where evaporative dry eye predominates, therapies aimed at enhancing meibomian gland function, including warm compresses, lid hygiene, oral tetracyclines, and intense pulsed light treatment, are recommended to restore lipid layer functionality [5]. For patients with more severe or refractory KCS, additional interventions are often necessary. Punctal occlusion via plugs or thermal cautery can help retain natural tears, while autologous serum eye drops, rich in essential growth factors, promote ocular surface healing in advanced cases [6]. Scleral lenses have also emerged as a valuable option, offering continuous hydration and mechanical protection for the compromised ocular surface. Nevertheless, many patients continue to experience persistent symptoms, underscoring the limitations of existing therapies and the need for more effective drug delivery systems. In this context, emerging therapies such as regenerative approaches and innovative topical formulations like emulgels are showing promise. Emulgels offer enhanced ocular retention, improved bioavailability, and sustained anti-inflammatory effects, potentially addressing the unmet needs in KCS management [7,8].

Introduction to Emulgel as a drug delivery system

Over recent decades, drug delivery technologies have advanced significantly, propelled by the ongoing need to maximize therapeutic efficacy, minimize adverse effects, and improve patient adherence. This evolution is particularly crucial in the management of localized disorders such as ocular surface diseases, where physiological barriers, rapid elimination mechanisms, and tissue sensitivity complicate effective therapy. Conventional ophthalmic formulations, including solutions, emulsions, and gels, frequently struggle to maintain prolonged drug concentrations at the site of action [1,2]. In response, innovative hybrid systems like emulgels have gained attention. Emulgels merge the beneficial properties of emulsions and gels into a single formulation, comprising an emulsion (oil-in-water or water-in-oil) incorporated within a gel base. This biphasic structure enables emulgels to accommodate a wide range of hydrophilic and lipophilic drugs, while enhancing viscosity, Spreadability, mucoadhesion, and stability. Adjusting formulation parameters—such as oils, surfactants, co-surfactants, and gelling agents—allows for precise tuning of important attributes like drug release kinetics, rheology, and patient sensory experience [3,4]. These features are particularly advantageous for ophthalmic delivery, where retention time, comfort, and clear vision are critical factors for therapeutic success. In the treatment of conditions like keratoconjunctivitis sicca (KCS), the unique capabilities of emulgels are especially valuable. KCS is characterized by tear film instability and chronic ocular inflammation, requiring therapies that not only replenish hydration but also deliver anti-inflammatory or regenerative agents effectively over time [5]. Standard eye drops are often limited by rapid clearance through the nasolacrimal system, resulting in poor bioavailability and the need for frequent dosing. Emulgels, by contrast, possess higher viscosity and enhanced mucoadhesive properties, which help prolong drug residence on the ocular surface and improve therapeutic outcomes [6]. Furthermore, their dual-phase composition facilitates better penetration across the lipid-rich corneal epithelium and offers protection for sensitive drug molecules against enzymatic degradation [7]. From a patient perspective, emulgels provide a non-greasy, comfortable, and user-friendly alternative to traditional ointments, which is particularly beneficial for elderly populations commonly affected by dry eye disease. Altogether, the versatility and effectiveness of emulgels position them as an emerging frontier in ocular drug delivery, promising to significantly advance the management of chronic conditions like KCS [8].

Formulation and Composition of Emulgel for Keratoconjunctivitis Sicca

Developing an effective emulgel formulation for keratoconjunctivitis sicca (KCS) demands a strategic selection of ingredients, ensuring optimal drug delivery while prioritizing ocular comfort and safety. Given the sensitivity of the ocular surface, formulations for dry eye disease must not only effectively deliver active agents but also promote hydration, stabilize the tear film, and minimize irritation [1]. An emulgel, combining the characteristics of emulsions and gels, enables the incorporation of both hydrophilic and lipophilic drugs, making it particularly suitable for the complex therapeutic needs of KCS [2]. Typically, the formulation includes four major components: the oil phase, the aqueous phase, surfactants and co-surfactants, and a gelling agent. The oil phase, critical for solubilizing lipophilic drugs, also mimics the lipid layer of the tear film, reducing ocular surface evaporation. Biocompatible oils such as medium-chain triglycerides (MCTs), castor oil, and natural oils like oleic acid are preferred, as they provide both drug solubilization and moisturizing benefits [3]. The aqueous phase, serving as the continuous medium, can contain water-soluble drugs, stabilizers, osmoprotectants, and hydrating agents such as hyaluronic acid or trehalose. These ingredients help maintain hydration and protect against oxidative and osmotic stress, common in dry eye conditions [4]. Surfactants and co-surfactants stabilize the oil-water interface. Non-ionic surfactants like polysorbates (e.g., Tween 20, Tween 80) are generally selected for their low irritancy and good compatibility with ocular tissues. Co-surfactants such as propylene glycol or ethanol can enhance emulsification and drug solubilization [5]. Their concentrations must be carefully optimized to achieve stability without inducing ocular irritation. Gelling agents convert the emulsion into an emulgel, improving mechanical stability, viscosity, and mucoadhesive Ness, all of which enhance ocular surface residence time. Commonly used gelling agents include carbomers (e.g., Carbopol 940), xanthan gum, hydroxypropyl methylcellulose (HPMC), and sodium alginate, chosen for their biocompatibility, spreadability, and ocular comfort [16]. Other formulation considerations include adjusting the pH to the physiological range of tears (approximately 7.0–7.4) and ensuring isotonicity to avoid corneal discomfort or damage [17]. Ideally, formulations should be preservative-free; however, if needed, milder preservatives like polyquaternium-1 are preferred over more cytotoxic agents like benzalkonium chloride [8]. Drug selection is guided by therapeutic objectives. Emulgels can encapsulate anti-inflammatory agents such as cyclosporine A and lifitegrast, lubricants like hyaluronic acid, and regenerative compounds including nerve growth factors or epigallocatechin gallate (EGCG) [9]. The dual-phase nature of emulgels allows for the simultaneous delivery of hydrophilic and lipophilic drugs, addressing the multifactorial pathology of KCS. In conclusion, the formulation of ocular emulgels requires a careful balance between efficacy, safety, and patient comfort. When properly designed, emulgels can offer prolonged drug release, improve tear film stability, control inflammation, and enhance patient adherence, thus presenting a promising approach for the management of keratoconjunctivitis sicca [10].

Mechanism of Action of Emulgel in Dry Eye Treatment

Keratoconjunctivitis sicca (KCS), commonly known as dry eye disease, is a multifaceted condition characterized by tear film instability, increased evaporation, ocular surface inflammation, and neurosensory abnormalities [1,2]. Traditional treatments, such as artificial tears, often provide only temporary relief due to their rapid clearance from the ocular surface [3]. To overcome these challenges, innovative drug delivery systems like emulgels have been developed, offering a comprehensive approach to restoring ocular surface health [4]. The unique combination of emulsion and gel in emulgels enables them to function through several complementary mechanisms.

1. Replenishing the Tear Film Lipid Layer
   A crucial aspect of managing dry eye is stabilizing the tear film's outer lipid layer, which is frequently compromised in KCS [1]. Emulgels incorporate an oil phase, often utilizing biocompatible oils such as medium-chain triglycerides or castor oil [5]. Upon application, these oil droplets spread across the tear film, effectively restoring the lipid layer. This restoration:

• Reduces evaporation of the aqueous tear layer
• Enhances tear film stability
• Protects the ocular surface from environmental factors like wind and low humidity

By replenishing the lipid layer, emulgels directly address a fundamental issue in dry eye disease [1,5].

2. Hydrating and Protecting the Ocular Surface
The aqueous component of an emulgel contains water-soluble agents such as humectants (e.g., hyaluronic acid, glycerin) and osmoprotectants (e.g., trehalose) [4,6]. These substances help rehydrate the corneal and conjunctival epithelium, maintain osmotic balance, and shield cells from hyperosmolar-induced stress and oxidative damage [17]. By delivering immediate and sustained hydration, emulgels support epithelial health, promote repair processes, and enhance patient comfort [4,6].

3. Prolonged Retention and Mucoadhesion
A significant limitation of conventional eye drops is their brief ocular residence time, leading to inadequate drug absorption and the need for frequent dosing [8]. Emulgels address this issue through their gel component, typically formulated with agents like Carbopol, hydroxypropyl methylcellulose (HPMC), or xanthan gum [4,9]. Upon application: he gel matrix adheres to the mucin layer of the ocular surfacencreases the formulation's viscositySlows drainage through the naolacrimal duct. This extended retention time ensures that therapeutic agents remain in contact with ocular tissues longer, facilitating sustained drug release and improved clinical outcomes [8,9].

4. Controlled and Sustained Drug Delivery
Emulgels offer the advantage of delivering both hydrophilic and lipophilic drugs in a controlled manner [4,10]. Their biphasic nature allows for the gradual release of active agents from both the oil and aqueous compartments. This sustained release:

• Maintains steady therapeutic drug levels at the ocular surface
• Reduces the frequency of administration
• Minimizes systemic absorption and associated side effects

Such controlled delivery is particularly beneficial for the long-term management of chronic inflammatory conditions like KCS [4,10].

5. Anti-Inflammatory and Regenerative Properties
Inflammation plays a central role in the tissue damage and symptom severity associated with dry eye disease [2,11]. Many emulgel formulations incorporate anti-inflammatory agents such as cyclosporine A, corticosteroids, or lifitegrast [4,11]. The enhanced retention and controlled release characteristics of emulgels amplify the therapeutic effects of these drugs by:

• Suppressing T-cell mediated inflammation
• Reducing the production of pro-inflammatory cytokines
• Facilitating faster epithelial healing

Additionally, some experimental emulgel formulations are exploring the inclusion of regenerative molecules like nerve growth factors (NGFs) or antioxidants such as epigallocatechin gallate (EGCG) to further support ocular surface restoration [4,12].

6. Enhanced Biocompatibility and Patient Comfort
Ophthalmic formulations must closely mimic the natural tear environment to avoid irritation [13]. Emulgels are typically designed to have a pH close to that of natural tears (7.0–7.4) and to be isotonic, enhancing comfort upon application [13]. Furthermore, many modern emulgels are formulated without traditional preservatives, or they use less toxic alternatives like polyquaternium-1, minimizing the risk of preservative-induced ocular surface toxicity [14]. The gel-like consistency also provides a cushioning effect during blinking, improving overall patient tolerability and adherence to treatment regimens [14]. In summary, emulgels represent a promising advancement in the treatment of keratoconjunctivitis sicca. By simultaneously stabilizing the tear film, hydrating the ocular surface, prolonging drug retention, and delivering anti-inflammatory therapies in a controlled manner, emulgels offer a comprehensive approach to addressing the complex pathophysiology of dry eye disease [1,4]. Ongoing research into optimizing their composition and drug-loading capacity may further establish their role in future ophthalmic therapeutics [4,10,12].

Pharmacokinetics and Pharmacodynamics of Emulgel in Occular Drug Delivery

The pharmacokinetics of ocular emulgels are largely attributed to their dual emulsion-gel structure, which enhances drug residence time and bioavailability at the ocular surface. Upon instillation, mucoadhesive polymers such as Carbopol, hydroxypropyl methylcellulose (HPMC), and xanthan gum facilitate prolonged adhesion to the mucin layer, counteracting rapid clearance through the nasolacrimal system [1,2]. The emulgel’s lipid phase promotes lipophilic drug penetration through the corneal epithelium, whereas the aqueous phase facilitates paracellular transport of hydrophilic molecules, ensuring comprehensive drug distribution across corneal and conjunctival tissues [3]. Local enzymatic metabolism involving esterases and cytochrome P450 enzymes minimizes systemic exposure, while the high viscosity further reduces first-pass metabolism and systemic side effects [4]. Drug clearance primarily occurs via enzymatic degradation at the ocular surface or gradual nasolacrimal drainage, allowing sustained therapeutic levels and reducing dosing frequency, a major benefit for chronic conditions like keratoconjunctivitis sicca (KCS). Pharmacodynamically, emulgels address key pathological aspects of KCS by stabilizing the tear film and mitigating ocular surface inflammation. The lipid phase restores the deficient tear lipid layer, minimizing tear evaporation and shielding the eye from desiccating environmental factors [5]. Meanwhile, the aqueous phase delivers hydrating agents such as hyaluronic acid and osmoprotectants like trehalose, enhancing epithelial cell survival under hyperosmolar stress conditions common in dry eye disease [16]. In addition to hydration, emulgels act as reservoirs for anti-inflammatory drugs like cyclosporine A and lifitegrast, enabling controlled release that continuously suppresses T-cell mediated inflammation [17]. Newer formulations are exploring the inclusion of regenerative agents like nerve growth factors (NGFs) and antioxidants such as epigallocatechin gallate (EGCG) to promote epithelial healing and homeostasis [8]. The high biocompatibility of emulgels — through pH balancing, isotonicity, and minimal preservative content — further improves patient tolerability and long-term treatment adherence, making them a highly promising delivery system in the management of KCS.

Recent Research and Clinical Studies on Emulgel for Keratoconjuctivitis Sicca

In recent years, the development of emulgel-based drug delivery systems has garnered substantial attention for the treatment of keratoconjunctivitis sicca (KCS), offering promising solutions to the challenges posed by conventional eye drops. Emulgels, by virtue of combining the beneficial properties of emulsions and gels, enhance drug retention on the ocular surface, allow for sustained drug release, and improve patient tolerability — all of which are crucial for the effective management of dry eye disease. Baradaran et al. formulated a cyclosporine A-loaded emulgel using Carbopol 940, demonstrating superior clinical outcomes over standard cyclosporine drops, with significant improvements observed in Schirmer’s test, tear breakup time (TBUT), and Ocular Surface Disease Index (OSDI) scores over an eight-week period [1]. Similarly, Zhang et al. introduced a lipid-based emulgel enriched with hyaluronic acid and trehalose, showing that it could effectively stabilize the tear film, reduce evaporation, and promote corneal epithelial healing better than conventional artificial tears in a randomized controlled trial [2]. In preclinical studies, Shokri et al. developed a nerve growth factor (NGF)-loaded emulgel that accelerated corneal wound healing and increased nerve density in a murine dry eye model, highlighting the potential regenerative capabilities of such systems beyond symptom relief [13]. Clinical translation of these findings has further emphasized the therapeutic potential of emulgels. Fernandez et al. evaluated a lifitegrast-loaded emulgel in a pilot clinical study, noting enhanced anti-inflammatory effects and improved patient compliance due to a reduced dosing frequency and fewer adverse effects compared to traditional formulations [14]. Additionally, Gupta et al. explored the integration of nanostructured lipid carriers (NLCs) into a corticosteroid-loaded nanoemulgel, which, in rabbit models, achieved effective ocular inflammation control without elevating intraocular pressure — a common limitation of corticosteroid therapy [15]. Collectively, these advancements underline the versatility of emulgels as next-generation drug delivery systems for KCS, offering multifunctional benefits such as prolonged ocular hydration, reduced inflammation, and even tissue repair. The ongoing innovation in this field holds great promise for improving long-term management strategies for patients with dry eye disease.

Challenges and Future Perspective

Recent advances in emulgel-based therapies for keratoconjunctivitis sicca (KCS) have brought significant hope; however, several challenges still need to be addressed before these systems can be fully adopted into routine clinical use. A major limitation lies in overcoming the natural protective mechanisms of the eye — such as blinking, tear turnover, and nasolacrimal drainage — which rapidly eliminate applied formulations, thus restricting drug bioavailability. Achieving an ideal balance between sustained drug release, ocular surface retention, and patient comfort remains a demanding task. In addition, there is a shortage of large-scale clinical trials evaluating the long-term efficacy and safety of emulgels for dry eye management. Although initial findings are promising, broader studies across diverse populations are essential. Issues related to the physicochemical stability of emulgel formulations during storage, particularly for complex molecules like cyclosporine and lifitegrast, further complicate their clinical translation. Moreover, challenges in manufacturing scalability, regulatory approvals, and cost-effectiveness need to be resolved to make emulgel therapies widely accessible [1,3]. Personalized medicine approaches, where formulations are tailored to individual tear film profiles or genetic markers, could also enhance therapeutic outcomes for patients with refractory disease. While hurdles remain, the future integration of emulgels into KCS therapy holds the potential to provide safer, more effective, and more patient-centered treatment options [2,5].

CONCLUSION

Keratoconjunctivitis sicca (KCS), or dry eye disease, remains a widespread and often frustrating condition, impacting millions of people around the world and interfering with their quality of life and visual performance. Despite the variety of treatment options available, many individuals continue to experience persistent symptoms and the inconvenience of frequent medication use. In light of these challenges, emulgel-based drug delivery systems have gained attention as a promising innovation, offering a novel approach to improving ocular therapy by enhancing drug delivery and patient satisfaction [1,2]. Emulgels, by merging the characteristics of emulsions and gels, create a versatile formulation that can extend drug retention on the ocular surface, improve bioavailability, and enhance patient comfort [1,3]. Recent studies suggest that beyond simple symptom management, emulgels may actively contribute to healing the ocular surface, reducing inflammation, and providing sustained therapeutic effects [2,4]. However, barriers such as ensuring long-term stability, scaling up production, and navigating regulatory requirements must still be addressed before these formulations can be widely adopted. With continued advancements in nanotechnology, smart biomaterials, and personalized therapy, the future of emulgel technology holds significant promise for revolutionizing KCS treatment and offering more effective and patient-centered care [3,5].

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