Department of pharmaceutics, K.K. College of Pharmacy.
Ocular drug delivery remains a major challenge in pharmaceutical research due to anatomical and physiological barriers such as tear turnover, nasolacrimal drainage, and corneal impermeability, which limit bioavailability of conventional eye drops to less than 5%. Sustained release formulations like ocular inserts and eye gels have emerged as innovative alternatives to overcome these limitations. Eye gels, particularly in-situ gelling systems, prolong precorneal residence time, enhance patient comfort, and improve therapeutic efficacy by offering diffusion-controlled or zero-order release. Ocular inserts, available in erodible and non-erodible forms, provide precise dosing, significantly higher tissue absorption, and extended release lasting from hours to several days. Comparative studies demonstrate that ocular inserts generally achieve superior bioavailability and therapeutic outcomes, including up to 42-fold higher tissue concentrations, while eye gels offer better patient compliance and ease of application. Advances in polymers, nanocarriers, 3D printing, and hybrid systems continue to expand the potential of both approaches. This review critically evaluates inserts and gels with respect to release kinetics, bioavailability, therapeutic efficacy, stability, irritation profile, shelf-life, and manufacturing costs, providing an updated perspective on which formulation may offer optimal ocular drug delivery for long-term therapy.
OVERVIEW OF OCULAR DRUG DELIVERY SYSTEMS
Ocular drug delivery has remained as one of the most challenging task for pharmaceutical scientists. The unique structure of the eye restricts the entry of drug molecules at the required site of action. Drug delivery to the eye can be broadly classified into anterior and posterior Segments. Conventional systems like eye drops, suspensions and ointments cannot be considered optimal in the treatment of vision threatening ocular diseases.[1] However, more than 90% of the marketed ophthalmic formulations are in the form of eye drops. These formulations mainly target the anterior segment eye diseases.[2]. Most of the topically applied drugs are washed off from the eye by various mechanisms (lacrimation, tear dilution and tear turnover) resulting in low ocular bioavailability of drugs. Moreover, human cornea comprising of epithelium, substantia propria and endothelium also restricts the ocular entry of drug molecules. [3]. As a result of these factors less than 5% of administered drug enters the eye. Alternative approaches like incorporation of permeation enhancers/cyclodextrins and increasing the viscosity of solutions did not provide any significant improvement. Recently many drug efflux pumps have been identified and significant enhancement in ocular drug absorption was achieved following their inhibition or evasion. But prolonged use of such inhibitors may result in undesirable effects [4]. To improve the retinal delivery of drugs, various local modes of administration, including intracameral, intravitreal and periocular routes, have been assessed. Intracameral injection refers to injection of drug solution in the anterior chamber of the eye. Up to 100 μl volume can be injected by this route. Intracameral injections are used in cataract surgery and for the management of diseases afflicting the anterior segment. This route of administration fails to deliver significant concentrations of drugs to the posterior segment.[5]. Dramatic changes have been observed in the field of ocular drug delivery over a decade. Insight into various membrane transporters/receptors present on the eye opened a new window of opportunities. Especially polar drug molecules, which fail to permeate ocular barriers, can be conveniently delivered via transporter/receptor targeted drug delivery systems.[6]. Although the topical route is non-invasive, handy and can be self-administered, there is a significant challenge to efficiently delivering drugs because of various anatomical and physiological barriers restricting the entry of therapeutic molecules into the ocular tissues.[7]. The eye gel formulation is typically prepared using the water bath stirring method, which ensures uniform mixing and gel formation. In contrast, ocular inserts are commonly prepared by the solvent casting method, which allows the formation of thin films suitable for sustained ocular drug delivery.
LIMITATION OF CONVENTIONAL OPHTHALAMIC PREPARATION
The main drawback of topical administration is still its comparatively poor effectiveness.
Because of the eye's distinct physiology and anatomy, drug delivery through the anterior segment is restricted and has low bioavailability. Because of blinking, tear turnover, and drainage through the nasolacrimal duct, a brief period of contact on the surface of the eye causes quick drug elimination. Because of this, very little of the medication is absorbed and gets to the intended tissues. [8,10]
Low bioavailability: The amount of medication that truly reaches intraocular tissues is restricted by anatomical and physiological barriers, such as the conjunctiva, tear film and corneal epithelium.
Frequent dosing: which may decrease patient convenience and compliance.
Dissolved drug instability: Certain medications can break down in solution before being administered.[8]
Use of preservatives: In order to maintain sterility, many preparations call for preservatives, which some patients may experience as irritation, toxicity, or allergic reactions. [8,10]
Restricted selection of excipients and preservatives: Formulation options are limited by safety requirements and chemical compatibility. Certain excipients are toxic in and of themselves.[10]
In an emergency, the dose cannot be stopped: The medication cannot be quickly taken out once it has been administered in the event of an adverse reaction.[8]
Possibility of ocular surface toxicity: Regular dosage and contact with medications or preservatives may cause harm to the ocular Surface.
The corneal epithelium's relative impermeability: restricts the delivery of medications, particularly those that target the anterior Segment.
Patient discomfort: Instillation can cause stinging, burning, or discomfort, often due to suboptimal pH or preservatives.[10].
NEEDS FOR SUSTAINED RELEASE FORMULATION
Ocular drug delivery faces several inherent limitations due to the unique protective mechanisms of the eye. Conventional formulations such as eye drops, despite their popularity, are associated with poor therapeutic efficiency. These challenges highlight the importance of developing sustained release formulations.
Increased bioavailability
Because of corneal impermeability, nasolacrimal drainage, and rapid tear turnover, less than 5% of the medication administered by conventional eye drops reaches the intraocular tissues. By extending the duration of the drug's residence at the site of absorption, sustained release systems increase bioavailability. [11,12]
Prolonged Precorneal Residence
Because eye drops usually have a residence time of two to five minutes, frequent instillation is required. Ocular inserts and in situ gels are examples of sustained release systems that prolong residence time and sustain therapeutic levels over extended periods of time.[13].
Adherence by Patients
Patient adherence is decreased by frequent dosing for long-term conditions like glaucoma. By lowering the frequency of doses, sustained release systems improve treatment results and compliance.[14]
Decreased risk of Systemic Absorption and Adverse Reactions
Adverse effects and systemic absorption are possible with drugs drained into the nasolacrimal duct. Ocular safety is enhanced and systemic exposure is decreased with localized sustained release.[15]
Consistent and Managed Therapy
By reducing variations in drug levels and guaranteeing a continuous therapeutic effect, sustained release systems provide controlled and predictable drug release. [16,17]
Better Clinical Results
Prolonged therapeutic drug levels are crucial in conditions like glaucoma, keratitis, conjunctivitis, and post-surgical inflammation. Formulations with sustained release guarantee consistent exposure, which lowers risks and enhances patient outcomes. [18]
ANATOMY OF THE EYE RELATED TO DRUG DELIVERY
One of the human body's most intricate organs is the eye. Three distinct layers can be identified in the human eye. The cornea and sclera make up the outer region. In addition to refracting and transmitting light to the lens and retina, the cornea shields the deeper components of the eye from infection and structural harm. The sclera creates a connective tissue layer that keeps the eye's shape and shields it from internal and external forces. The limbus is where the sclera and cornea are joined. The conjunctiva is a transparent mucous membrane that covers the visible portion of the sclera.[19]. The iris, ciliary body, and choroid make up the middle layer of the eye. The ciliary body regulates the strength and form of the lens and is the location of aqueous production; the iris regulates the pupil's size and, consequently, the quantity of light that reaches the retina; and the choroid is a vascular layer that supplies oxygen and nutrients to the outer layers of the retina. The retina, a sophisticated, layered structure of neurons that absorbs and processes light, is the innermost layer of the eye. The aqueous, vitreous, and lens are the three transparent structures that are encircled by the ocular layers.[19]
STRUCTURE OF EYE
Figure No 1: Structure Of Eye
ANTERIOR SEGMENT:[20]
The anterior chamber is a fluid-filled area that drains through the drainage angle and contains aqueous humor, which keeps eye pressure stable.
Cornea: The cornea is a transparent, dome-shaped structure that directs 70% of light into the eye.
Iris and pupil: Iris regulates light entry by controlling pupil size.
Lens: With the help of zonules, the lens modifies shape for near vision, focuses light, and provides 30% of the focusing power.
POSTERIOR SEGMENT:
Vitreous cavity: Gel-like vitreous humor fills the vitreous cavity.
Retina: The light-sensitive layer that transforms light into electrical signals is called the retina.
Macula: Sharp central vision is provided by the macula. Side vision is made possible by the peripheral retina. The retina has special cells called photoreceptors and cells changes light into energy that is transmitted to the brain. They are two types of photoreceptors rods and cones.
Rods: Night vision, black and white.
Cones: Visual acuity and color.
For vision, the optic nerve sends signals from the retina to the visual cortex of the brain.
Figure No 2: Ocular Drug Delivery Barriers
FACTORS AFFECTING OCULAR BIOAVAILABILITY
Tear film dynamics: Blinking and rapid tear turnover (1–3 µL/min) dilute and wash out the drug from the precorneal region. Since most eye drops deliver 30 to 50 µL, whereas normal tear volume is only 7 to 10 µL, the excess quickly drains away, reducing drug absorption.[21]
Nasolacrimal drainage: Systemic absorption results from the nasolacrimal duct losing a significant amount of the administered medication. In addition to decreasing ocular bioavailability, this can also result in systemic side effects, such as cardiovascular effects using ophthalmicβ-blockers.[22]
Corneal barrier: The three primary layers of the cornea are the endothelium (less resistant but still a barrier), stroma (hydrophilic, restricts lipophilic drugs), and epithelium (lipophilic, restricts hydrophilic drugs). Due to this dual nature, medications need to have an Drugs must have the ideal ratio of hydrophilicity to lipophilicity due to this dual nature in order to penetrate efficiently.[23]
Drug physicochemical properties: Smaller molecules penetrate more easily, so molecular size is important. Corneal penetration is enhanced by moderate lipophilicity and the presence of a non-ionized fraction. Drug availability is restricted by poor solubility, and the concentration of free drug available for absorption is decreased by high protein binding to tear proteins.[21]
Formulation factors: To prevent reflex tearing and discomfort, the pH and tonicity should be adjusted to be close to physiological tear fluid (pH ~7.4, isotonic with 0.9% NaCl). While more viscosity lengthens the duration of a drug's residence, too much viscosity can cause vision blur. In contrast to traditional drops, new dosage forms such as gels, emulsions, nanoparticles, and ocular inserts offer sustained release and enhanced retention, while smaller particle sizes enhance dissolution and corneal penetration.[22]
Patient-related factors: Factors pertaining to patients Drug retention is impacted by age-related changes in blinking rate and tear production. Permeability and absorption can be changed by ocular disorders like dry eye, conjunctivitis, or corneal damage. Effective bioavailability is also greatly decreased by patients using improper instillation techniques (such as blinking right after dosing or missing the conjunctival sac).[23]
OCULAR INSERTS: Ocular inserts are small, delicate, sterile, stratified solid pieces of a device placed into the conjunctival sac to deliver drugs.
Two types of ocular inserts
1. Erodible.
2. Non-erodible.
Ocular inserts are also known as ocuserts. They offer the advantages of increasing the residence time, improving the bioavailability of drugs, and reducing the dosing frequency. Within 24 hours, the inserts may dissolve completely. The inserts' erosion majorly depends on the type and concentration of polymers used. The non-erodible inserts are made of either matrix or a reservoir that helps sustain the drug release. [24,25]
CLASSIFICATION OF OCULAR INSERTS [26,27,28,29]
Figure No 3: Classification Of Ocular Inserts
INSOLUBLE OPHTHALMIC INSERTS
These are classified into three groups:
Their main disadvantage is insolubility, requiring removal after use.
Figure No 4: Mechanism of Ocular Drug Delivery
EYE GEL
Eye gel refers to a semi-solid, sterile, aqueous formulation designed for ophthalmic use. It contains a viscous gel matrix that allows the gel to remain longer on the eye surface, providing extended lubrication and protection compared to regular eye drops. Eye gels are usually transparent and formulated to be spreadable and comfortable when applied to the eye's conjunctiva. Their unique viscosity contributes to longer-lasting relief from symptoms such as dryness, soreness, or irritation.[30]
CLASSIFICATION OF EYE GEL
By Solvent:
By Structure:
By Polymer:
FIGURE NO 5: MECHANSIM OF EYE GEL
COMPARATIVE ANALYSIS OF OCULAR INSERTS AND EYE GEL
Ocular Inserts – Drug Release Kinetics
For drug release, ocular inserts frequently use processes like diffusion, osmosis, and bioerosion [31]. With a steady release over 20–200 days, many modern inserts are made for zero-order kinetics, which increases patient compliance in long-term conditions like glaucoma[32]. To achieve predictable release profiles, the polymer composition (e.g., PEG content, erodible matrices) and device geometry are customized[33]. Inserts may also adhere to Higuchi's square-root time model or Fickian diffusion, depending on the system (eroding, swelling-controlled, or diffusion-based) [34]. Additionally, Case II transport can be seen in inserts composed of biodegradable/soluble polymers, enabling controlled, zero-order release with matrix degradation [35].
Eye Gels - Drug Release Kinetics
When exposed to cul-de-sac conditions, eye gels—particularly in situ gel-forming systems—release drugs through a sol-to-gel transition [36]. Viscosity, swelling behavior, and interaction with ocular tissues all affect drug release from gels [37]. Zero-order or Higuchi diffusion-controlled models are frequently fitted by formulas containing polymers like Poloxamer or Carbopol [38]. Gels' sustained release promotes longer therapeutic action with fewer instillations and helps prevent burst effects [39]. As a result, zero-order release kinetics are thought to be optimal for ocular gels, enhancing patient convenience and residence time [40].
Table No 2: Comparison Of Ocular Inserts and Eye Gels in Drug Release
|
System |
Main Release Mechanism |
Typical Kinetics |
Duration |
|
Ocular Inserts |
Diffusion, Erosion, Osmosis |
Zero-order, Higuchi |
8h-200 days |
|
Eye Gel |
Diffusion, Swelling |
Zero-order, Higuchi |
Up to 8h – 24 h |
Figure No 6: Ocular Inserts Vs Eye Gel: Release Kinetics
COMPARATIVE STUDY OF BIOAVAILABILITY
Recent research continues to show that ocular inserts provide substantially increased bioavailability over gels and other formulations, but advanced in-situ gels are also closing the gap with improvements in sustained release and patient compliance.
Eye Gels [41]
Thermo-responsive or ion-activated in-situ gels begin as liquids or drops and solidify when they come into contact with the eye, significantly extending residence time and lowering dosage frequency. Optimized gels like ganciclovir in-situ gel or moxifloxacin systems demonstrated greater ocular penetration, higher concentration profiles (Cmax and AUC), and improved patient tolerance when compared to commercial drops and solutions, although detailed comparisons to inserts are still less common in literature.
Ocular Inserts [42,43]
The gold standard for optimizing ocular bioavailability is still ocular inserts, which can boost iris-ciliary body absorption by up to 24 times and conjunctival absorption by up to 42 times over traditional drops—numbers that still surpass those of the majority of in-situ gels. Although inserts provide precise dosage and controlled release, they have disadvantages such as discomfort, displacement risk, and potential visual interference.
Table No 3: Comparison Of Ocular Inserts and Eye Gels in Bioavailability
|
Feature |
Eye Gel |
Ocular Inserts |
|
Drug Residence Time |
Hours (extended by gel formation) |
Hours to days (longest contact time) |
|
Bioavailability Increase |
Moderate (5-15%) |
High (up to 42x in tissues) |
|
Release Profile |
Sustained, diffusion- controlled |
Controlled, programmable release |
|
Dosing Frequency |
Reduced vs drops |
Lowest dose |
THERAPEUTIC EFFICACY
The therapeutic efficacy of eye gels and ocular inserts varies significantly based on formulation design, drug release mechanisms, and clinical application. Both systems demonstrate superior therapeutic outcomes compared to conventional eye drops.
Gels show remarkable clinical improvements
Clinical Disease Management [46]
OCULAR INSERTS: SUPERIOR SUSTAINED EFFICACY
Pharmacokinetic Benefits:[47]
• Ocular inserts enhance iris-ciliary body absorption by 24 times over traditional drops. Conjunctival absorption is increased by 2.7–42 times over eye drops.
• According to AUC ratios, eye drops only achieve 1.4 times the drug exposure in the iris-ciliary body as opposed to aqueous humor, whereas inserts achieve 9 times.
Clinical Result [47,48]
• Glycerogelatin-based inserts showed improved local therapeutic effects and sustained release profiles with decreased systemic absorption.
• Inserts eliminate dose variability associated with liquid formulations by providing precise dosing and full drug retention at the administration site.
Table No 4: Comparison of Ocular Inserts and Eye Gels in Therapeutic Efficacy
|
Parameter |
Eye Gels |
Ocular Inserts |
|
Drug Residence Time |
6-12 hours (extended) |
Hours to days (maximum) |
|
Peak Concentration |
44% higher than drops |
Up to 42x higher tissuse levels |
|
Dosing Frequency |
2-3 Times daily (reduced) |
Lower due to foregin body sensation |
|
Symptom Improvement |
50-67% improvement |
Sustained improvement with precise control |
|
Systemic Side Effects |
Reduced versus drops |
Minimal systemic exposure |
COMPARATIVE FINDINGS FROM THE EYE IRRITATION TEST
Ocular irritation is commonly assessed using tests like HET-CAM, Draize rabbit test, or in vitro tissue models. In studies
Ocular Insert Eye Irritation Test [49, 51, 54, 55]
When tested in vitro and in vivo, ocular inserts usually cause little ocular irritation. At first, they might produce a slight foreign body sensation, which could cause some temporary discomfort or tearing but no serious harm. In comparison to controls, ocular inserts in animal experiments showed very little redness, inflammation, or tear production. The risk of irritation is greatly decreased when biocompatible polymers and preservative-free formulations are used in inserts. Zero-order drug release is the goal of inserts. reducing the highest concentrations that cause irritation.
Test for Eye Gel Irritation [50, 52]
According to validated in vitro tests like the EpiOcular Eye Irritation Test (EIT), eye gels, particularly those that use chitosan and pluronic F-127 polymers in pH and thermosensitive in-situ gels, cause very little irritation. These gels support patient comfort by meeting ophthalmic standards for clarity and transparency and by not appreciably increasing redness or inflammation. However, if used, preservatives such as benzalkonium chloride (BAK) may cause toxicity to the ocular surface after repeated use.
Table No 5: Comparative Summary
|
CRITERION
|
OCULAR INSERTS |
EYE GEL |
|
Irritation |
Minimal chemical irritation; foreign body sensation common. |
Minimal irritation; transient blurred vision possible. |
|
Patient Compliance |
Mild discomfort; rare insert migration |
Higher due to ease of application |
COMPARATIVE STUDY OF STABILITY AND SHELF LIFE
A comparative study of the stability and shelf life of ocular inserts and eye gels shows that ocular inserts often exhibit greater stability and longer shelf life due to their low moisture content, exclusion of preservatives, and solid matrix, while eye gels—being water-based—are generally more prone to microbial growth, degradation, and require shorter shelf lives unless preserved.
Ocular Insert [49, 56, 57, 58]
Studies of ocular inserts, such as those containing gatifloxacin or ketorolac tromethamine, show that they maintain their physical and chemical stability for extended periods of time, usually at room temperature as well as under accelerated conditions, with little drug degradation and maintained integrity for at least six months. When properly packaged, such as in aluminum foils, inserts retain their sterility and exhibit no signs of microbial growth. The extended shelf life—often longer than similar aqueous-based formulations like gels—is a result of the solid, water-free nature, which helps prevent hydrolytic degradation and microbial contamination.
Eye gel [59, 60]
If eye gels are kept in the right packaging, they should remain stable at room temperature for a few months (one to six months). Their water content, which raises the possibility of microbial growth and some degree of hydrolytic or oxidative degradation, is the primary factor limiting their shelf life. Gels without preservatives have a shorter shelf life and typically require cold storage, whereas preserved gels have a longer shelf life. Recent studies have demonstrated increased stability and shelf lives for gels containing nanoparticles (CS-NPs, PCL-NPs).
COMPARATIVE STUDY OF MANUFACTURING COST
Manufacturing of Ocular Inserts [61]
• Several techniques, such as solvent casting, compression molding, hot melt extrusion, and 3D printing, are used to make ocular inserts. In order to achieve sustained release, inserts usually need precise control over the composition of the polymer matrix, drug loading, membrane permeability, and device size.
Because inserts are solid, sterile handling and packaging are necessary to preserve sterility and mechanical integrity.
• Single-step, solvent-free, scalable, and economical manufacturing solutions are provided by recent technologies such as hot-melt extrusion and laser-based fabrication.
• Automation improves batch consistency and decreases manual labor, but production complexity is higher than with gels.
Manufacturing of Eye Gels [62]
Cost Comparison
Comparison Of Pharmacological And Clinical Parameters
Table No 6: Comparison of Pharmacological and Clinical Parameters
|
Parameter |
Eye Gels |
Ocular Inserts |
|
Drug Residence Time |
6-12 hours (extended) |
Hours to days (maximum) |
|
Peak Concentration |
44% higher than drops |
Up to 42x higher tissue levels |
|
Patient Compliance |
91% good/very good tolerance; minimal discomfort |
Lower due to foreign body sensation; possibility of irritation and migration |
|
Dosing Frequency |
2-3 times daily (reduced) |
Once daily or less (prolonged action) |
|
Symptom Improvement |
50-67% clinical improvement (ex: dry eye relief) |
Sustained improvement with precise drug release control |
|
Systemic Side Effects |
Reduced versus eye drops |
Minimal systemic exposure due to local ocular delivery. |
RECENT ADVANCES AND INNOVATIONS
Recently, new gels based on sodium hyaluronate have been developed for lacrimal occlusion; these gels have the potential to be effective dry eye treatments that eventually replace traditional punctal plugs because they improve corneal health, lessen ocular inflammation, and reduce dry eye symptoms. A 2025 study that was presented at SECO claims that this gel offers significant clinical benefits for the treatment of dry eye disease. Multilayer, polymer-based drug delivery systems that prolong the duration of drug residence on the surface of the eye and allow for sustained drug release are at the heart of ocular insert innovations. These soluble, insoluble, or bioerodible inserts are intended to improve drug bioavailability, boost patient compliance, and reduce systemic absorption. Recent developments include membrane-bound inserts, mucoadhesive forms, and nanoparticle-based systems. Advances also involve in-situ gel formations and nanocarriers that enhance penetration and therapeutic efficacy.
CONCLUSION
Recent advances in ocular drug delivery underline the superior therapeutic and pharmacokinetic profiles of both eye gels and ocular inserts versus conventional ophthalmic preparations. Ocular inserts remain the gold standard for achieving maximum drug bioavailability, sustained tissue exposure, and precise dosing; however, eye gels—especially in situ gel systems—are rapidly closing the gap by offering extended residence time, improved comfort, and better patient compliance. The choice between the two systems should be guided by disease-specific requirements, patient preferences, and formulation stability considerations. Continued innovation in polymer science, mucoadhesion, and manufacturing technologies is likely to further enhance these delivery platforms, enabling tailored, patient-centered ocular therapies with optimal clinical outcomes.
ACKNOWLEDGEMENT
We sincerely thank our Management, Dr. A. Meena, Principal and Dr. A. Shanthy, Vice-Principal for their encouragement and support for this review work.
REFERENCES
Ganesh S., Karthick K.*, Pravin S., Eye on Innovation: A Comparative Review on Ocular Inserts and Eye Gel for Enhanced Therapeutic Efficacy and Better Ocular Drug Delivery, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 9, 1586-1602 https://doi.org/10.5281/zenodo.17118772
10.5281/zenodo.17118772
