Ocular Drug Delivery Systems

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Technical Review Article | Open Access | Published 16th December 2025

Ocular Drug Delivery Systems

Nandamu Bhargav; Dr.K.V.Subba. EJPPS | 304 (2025) | https://doi.org/10.37521/ejpps30305

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Abstract

The field of Ocular Drug Delivery Systems (ODDS) has undergone a profound transformation since the late 20th century, necessitated by the fundamental failures of conventional topical eye drops. While eye drops remain the standard, their efficiency is severely limited by the eye's intricate structure and formidable natural barriers, resulting in less than 5% drug bioavailability. This inefficiency forces frequent dosing, leading to poor patient compliance and increasing the risk of both local irritation and unwanted systemic absorption. Starting around 1999, a dramatic paradigm shift was initiated, driven by rapid advancements in materials science, nanotechnology, and biotechnology. This era of intense innovation has moved research away from simple aqueous solutions toward sophisticated, advanced delivery strategies capable of overcoming anatomical and physiological defences, aiming for improved efficacy, targeted delivery, and sustained therapeutic action within both the anterior and posterior segments of the eye

Key-words: Ocular Drug Delivery, Nanoparticles, Ocular Implants, Hydrogels, Posterior Segment, Gene Therapy, Bioavailability, Blood-Retinal Barrier

Introduction

Current methods for treating ocular diseases, such as administering topical eye drops, are highly inefficient; less than 5% of the drug reaches the internal eye tissues due to the eye's natural defences, leading to low drug effectiveness, frequent dosing, poor patient compliance, and unwanted side effects. To solve this, intense research since the late 1990s has focused on developing innovative Ocular Drug Delivery Systems (ODDS) with the core goal of overcoming these barriers to achieve high bioavailability, sustained and controlled drug release, and effective targeting of both the anterior and posterior segments of the eye. Key advancements reviewed in this field include the refinement of technologies such as mucoadhesion and in situ gelation, the widespread application of nanotechnology, and the successful clinical realization of long-acting implants for chronic retinal diseases. Increasing the liquid viscosity was the initial logical step to improve drug delivery. By incorporating polymers such as hydroxypropyl methylcellulose (HPMC), the speed at which tears and blinking clear the liquid drop is effectively reduced. This crucial change prolongs the drug's contact time with the cornea, enhancing its therapeutic window. The concept was then advanced by utilizing mucoadhesive polymers. Materials such as chitosan and polyacrylic acid derivatives (e.g., carbomer) are engineered to interact physically and chemically with the tear film's mucin layer. This interaction functions as a temporary "anchor," substantially extending the drug's residence time on the ocular surface. This maximization of drug contact time is key to improving absorption into the anterior segment of the eye.

The most modern iteration involves thiolated polymers. These cutting-edge materials take the principle of adhesion further by forming robust covalent bonds with the eye's surface proteins. This chemical bonding provides a superior, more dependable, and reliable adhesion, offering the longest and most consistent drug retention yet. These advancements represent a continuous evolution toward overcoming the eye's natural clearance mechanisms to optimize drug effectiveness

Advanced Ocular Drug Delivery Strategies

In Situ Gelling Formulations: These "smart" liquid drops are administered easily but quickly transform into a viscoelastic gel upon contact with the eye, creating a sustained-release drug depot. This phase change is triggered by specific physiological changes, such as warming to eye temperature (e.g., Poloxamer 407), neutralization of pH by tears, or the presence of ions in tear fluid (e.g., gellan gum).

Nanotechnology and Particulate Carriers: This involves using microscopic systems (nanoparticles, liposomes, niosomes, and dendrimers) to effectively cross ocular barriers. By encapsulating the drug, these carriers enhance stability, improve penetration, and significantly prolong the drug's contact time with anterior tissues.

Ocular Protective Barriers

To understand the necessity of these advanced systems, the eye's natural defences must be recognized:

Static (Anatomical) Barriers: These are the physical structures that restrict drug passage. The most significant is the cornea, which is the primary entry point but features an alternating lipophilic-hydrophilic-lipophilic layering (epithelium, stroma, endothelium) that prevents both purely water-soluble and purely fat-soluble drugs from crossing completely.

Dynamic (Physiological) Barriers: These are active processes that flush out substances, drastically reducing drug residence time and bioavailability. They include blinking, tear production, and nasolacrimal drainage.

Dynamic (Physiological) Barriers to Ocular Drug Delivery:

The dynamic (physiological) barriers of the eye actively and efficiently remove drugs, severely limiting the effectiveness of conventional eye drops. The most immediate defences are the Tear Film and Turnover, a constant secretion, circulation, and drainage process that acts as a natural washing system to sweep away applied medicine. This action is reinforced by the Blinking Reflex, which physically shortens the drug's residence time on the ocular surface. Inside the eye, Aqueous Humour Dynamics (constant production and drainage of fluid in the anterior chamber) dilutes any drug that manages to penetrate the cornea, limiting the therapeutic concentration. Finally, for drugs targeting the back of the eye (e.g. the retina), the Blood–Ocular Barriers (comprising the blood–aqueous and blood–retinal barriers) pose the most stringent defence. These barriers consist of cells with tight junctions that strictly regulate the movement of molecules from the systemic circulation into the delicate internal structures, making effective delivery to the retina exceptionally difficult.

Additional Anatomical Barriers

The Conjunctiva and Sclera: While the conjunctiva is more permeable than the cornea, it acts as an inefficient route because its rich network of blood and lymphatic vessels rapidly sweeps absorbed drugs into the systemic circulation rather than the inner eye. The sclera, the eye's tough outer layer, is a potential route to the back of the eye, but its inherent permeability is low.

The Blood-Retinal Barrier (BRB): This is the most formidable obstacle for treating retinal diseases. Acting like an impenetrable shield, the BRB consists of two layers of cells with tight junctions (the inner and outer BRB) that severely restrict the passage of drugs from the bloodstream into the delicate neural retina and vitreous humour. This makes administering drugs systemically (body-wide) highly inefficient for targeting the posterior segment.

The eye's Dynamic (Physiological) Barriers rapidly remove topically applied drugs, severely limiting their effectiveness:

Tear Film Dynamics: A standard eye drop (30-50 μL) immediately overloads the eye's tiny resident tear volume (7-10 μL), causing most of the drug volume to be instantly expelled.

Tear Turnover and Blinking: The tear film is constantly renewed at a rate of about 16% per minute, limiting the drug's residence time to a mere 2-5 minutes. Blinking further accelerates this rapid clearance.

Nasolacrimal Drainage: Unabsorbed drug is swiftly drained through the nasolacrimal duct into the nasal cavity. From there, it can enter the body's systemic circulation, posing a risk of unwanted side effects, such as cardiovascular issues from glaucoma medications.

Prior to 1999, the market relied mostly on simple dosage forms such as solutions, suspensions, and ointments. The major limitations of these traditional methods—rapid drug elimination and poor ocular bioavailability—highlighted a critical need for innovation. This spurred the development of modern technologies centred on a primary objective: to prolong the drug's contact time (residence time) with the ocular surface. Enhancing residence time is crucial for improving therapeutic effectiveness, reducing dosing frequency, and minimizing side effects, which ultimately leads to better patient compliance and clinical outcomes.

Viscosity-Enhanced Formulations and Mucoadhesive Systems

Viscosity-Enhanced Formulations provide a foundational strategy to improve conventional eye drops. This approach directly addresses the issue of rapid drug elimination by increasing the liquid's thickness (viscosity). The core goal is to slow down drainage and tear washout, thereby prolonging the drug's contact time with the precorneal area. This extended residence time boosts drug absorption and therapeutic effectiveness and may also allow for less frequent dosing. This viscosity enhancement is achieved by incorporating safe, biocompatible polymers such as polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), and carboxymethyl cellulose (CMC), which also offer a soothing, lubricating effect. Although this method doesn't help drugs penetrate to deeper eye tissues, it remains a key, fundamental advancement in modern eye drop design.

The Evolution to Mucoadhesive Polymers

The strategy of enhancing drug residence time evolved significantly with the introduction of mucoadhesive polymers, which are a major improvement over simple viscosity agents. These materials are specifically designed to chemically and physically interact with the mucin layer of the tear film, acting as an anchor. By forming bonds (such as hydrogen or electrostatic interactions) with mucin, mucoadhesive polymers allow the drug formulation to resist natural clearance mechanisms such as blinking and tear turnover much more effectively. This significantly extends the drug's contact time with ocular tissues, boosting absorption and bioavailability, which leads to better therapeutic results with potentially fewer doses. Common examples include chitosan, hyaluronic acid, and carbomers. Notably, the highly researched, positively charged natural polymer chitosan offers the dual benefits of excellent mucoadhesion and acting as a penetration enhancer to help drugs cross the corneal barrier

The advancement in eye drop formulation relies on increasingly sophisticated polymers to enhance drug retention. Key examples include:

Hyaluronic acid: A naturally occurring substance valued for its high viscosity and excellent moisture-retention properties.

Polyacrylic acid derivatives (e.g., carbomer): These polymers swell dramatically upon contact with tears to form strong gels, which leads to prolonged drug retention on the eye.

Thiolated polymers: Representing the most advanced class, these polymers contain thiol groups that form robust, permanent covalent bonds with the eye's mucin proteins. This unique mechanism creates a much stronger and more reliable form of adhesion than simple physical attraction, maximizing the drug's time on the ocular surface and significantly enhancing therapeutic effect.

In Situ Gelling Systems

In situ gelling systems are advanced ophthalmic drug formulations that combine the ease of a liquid drop with the sustained benefits of a gel. Applied as a low-viscosity liquid, the solution rapidly transforms into a viscoelastic gel upon contact with the eye's cul-de-sac. This quick sol-to-gel phase transition is intentionally triggered by specific physiological cues, such as the eye's temperature (e.g., poloxamers), changes in pH (e.g., carbopol), or the presence of specific ions in tear fluid (e.g., gellan gum). The formation of this gel depot is critical because it significantly prolongs drug retention by resisting washout from tear flow and blinking. This sustained-release mechanism ultimately enhances drug absorption and therapeutic efficacy, offering better control over delivery and potentially improving patient compliance by reducing the required dosing frequency.

Temperature-Triggered Systems

Thermo-sensitive in situ gelling systems represent a major advance in eye drop formulation. These systems, which include polymers such as Poloxamer 407, are initially stored and administered as an easy-to-use low-viscosity liquid at refrigerated temperatures. Upon reaching the physiological eye temperature of around 34∘C, the polymer chains rapidly reorganize, triggering a quick liquid-to-viscoelastic gel transformation. This in situ gel adheres to the ocular surface, drastically reducing drug washout (clearance) and enabling sustained drug release. The outcome is improved therapeutic efficacy and better patient compliance due to the need for fewer applications

pH-Triggered Systems

pH-sensitive in situ gelling systems use a shift in pH to trigger the transition from a liquid to a gel. Polymers, such as cellulose acetate phthalate (CAP), are formulated in an acidic liquid for easy application. Once instilled, the nearly neutral pH of the tear film (∼7.4) triggers the polymer to swell and rapidly gel. This resulting viscoelastic gel adheres to the ocular surface, effectively reducing drug washout and enabling prolonged drug retention and sustained delivery, thereby enhancing therapeutic efficacy and patient compliance.

Ion-Triggered Systems

Ion-sensitive in situ gelling systems use polymers that gel in response to the salts present in tear fluid. Polymers such as gellan gum (Gelrite®) and sodium alginate rapidly undergo cross-linking when exposed to cations (such as Na+, K+, and Ca2+) found in tears. This ionic interaction immediately forms a sustained-release gel matrix on the ocular surface, significantly prolonging the drug's residence time. A successful clinical application is Timolol Maleate Gelling Solution (Timoptic-XE®), which treats glaucoma by increasing drug bioavailability and reducing the required dosing frequency, ultimately improving patient compliance.

Particulate Carrier Systems:

The integration of nanotechnology has been the most significant advancement in Ocular Drug Delivery Systems (ODDS) since 1999. By using nanoparticulate carriers to encapsulate drugs, this technology offers several critical benefits: it protects drugs from degradation, enhances their solubility, allows for controlled and sustained release, and facilitates targeted delivery to specific eye tissues. Ultimately, nanotechnology improves therapeutic efficacy, minimizes side effects, and reduces dosing frequency, marking a promising frontier for more effective and patient-friendly ophthalmic treatments.

Nanoparticles

Types of Nanoparticle Carriers

Polymeric Nanoparticles: These are typically made from biodegradable polymers such as poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), and chitosan. Their small size allows for better penetration of the corneal and conjunctival barriers and provides sustained drug release for an extended period. Their surfaces can be chemically modified to enhance mucoadhesion (e.g., using chitosan) or to target specific cells.

Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC): These are lipid-based carriers that remain solid at room temperature. They merge the benefits of controlled release (from polymers) with high biocompatibility (from lipids). They are especially effective for lipophilic (fat-soluble) drugs and have shown great potential in enhancing corneal penetration.

Liposomes

Liposomes are versatile, tiny spherical vesicles composed of phospholipid bilayers enclosing an aqueous core. Their amphiphilic structure allows them to encapsulate both hydrophilic drugs (in the core) and lipophilic drugs (in the bilayer), making them highly suitable carriers. They are biocompatible and biodegradable, ensuring safety for the eye. Because their structure resembles cell membranes, liposomes interact efficiently with corneal cells, facilitating drug uptake primarily via endocytosis. Their effectiveness can be further enhanced by cationic (positively charged) surface modification, which promotes electrostatic binding to the negatively charged ocular surface (e.g. mucins). This increased adhesion significantly prolongs the drug's residence time and penetration, improving overall therapeutic outcomes.

Niosomes

Niosomes are drug carriers similar to liposomes, but they utilize non-ionic surfactants instead of phospholipids, making them a more stable and cost-effective option. Their structure allows them to effectively encapsulate both hydrophilic and lipophilic drugs, offering protection and enabling controlled drug release. By significantly increasing drug retention time and facilitating better penetration, Niosomes have successfully improved the ocular bioavailability of several drugs, establishing them as a valuable and affordable alternative in advanced ocular drug delivery systems

Dendrimers

Dendrimers are highly branched, precisely structured macromolecules with a defined three-dimensional architecture and a high density of functional surface groups. This unique structure allows them to encapsulate or conjugate therapeutic agents, and their surfaces can be modified to improve drug solubility, permeability, or attach targeting ligands. In ocular delivery, their nanoscale size and structure enable them to enhance the solubility of poorly water-soluble drugs, increase residence time on the eye surface (as seen with pilocarpine formulations), and facilitate better penetration through ocular barriers. Consequently, dendrimers are a promising, versatile platform for targeted and controlled ophthalmic drug delivery.

Ocular Emulsions

Cationic emulsions are an important, distinct advancement in ocular drug delivery, utilizing positively charged lipid droplets. These droplets interact electrostatically with the negatively charged mucin layer on the eye's surface, effectively acting as an anchor. This mechanism significantly enhances the drug's residence time by resisting rapid clearance from blinking and tear turnover. By prolonging contact with the cornea and conjunctiva, cationic emulsions improve drug absorption and bioavailability, leading to better therapeutic results. A notable clinical success is Restasis® (cyclosporine A) for dry eye disease, which also provides a soothing, lubricating effect, demonstrating the platform's potential for enhanced treatment efficacy and patient comfort

Conquering the Posterior Segment

The treatment of serious diseases affecting the back of the eye (the posterior segment), such as Age-related Macular Degeneration (AMD), Diabetic Macular Edema (DME), and uveitis, has been fundamentally revolutionized. Before the 2000s, delivering drugs to this area was extremely challenging, as traditional eye drops and systemic drugs couldn't reach therapeutic levels. Modern advancements, including intravitreal injections and sustained-release implants, now allow for the direct and controlled delivery of medication, dramatically improving clinical outcomes and the quality of life for patients.

Ocular Implants

Ocular implants are sterile, solid devices surgically placed inside the eye to provide a controlled, sustained release of medication over months or years, which has revolutionized the treatment of chronic posterior segment diseases by ensuring prolonged effects and improving compliance. There are two main types: Non-Biodegradable Implants, such as Retisert® and the smaller, injectable Iluvien® (both containing fluocinolone acetonide), which deliver drugs for 2.5 to 3 years but require surgical removal. Conversely, Biodegradable Implants, such as the PLGA-based Ozurdex® (dexamethasone), are injected and deliver therapeutic levels for up to 6 months before safely dissolving into the body, eliminating the need for a second surgery.

Particulate Systems for Posterior Delivery

Current research in ocular drug delivery is focused on finding less invasive methods to treat posterior segment diseases, aiming to replace frequent intravitreal injections. The primary strategy involves engineering nanoparticles and microparticles for delivery via topical or periocular routes (such as subconjunctival injections). These particles are designed to either penetrate the tough scleral barrier or form a localized drug depot near the eye's surface, allowing the medication to slowly diffuse to the posterior tissues and maintain therapeutic levels. The potential benefits include reduced risks (e.g., from infection and retinal detachment) and improved patient comfort and compliance. While challenges remain in ensuring sufficient drug penetration, retention, and minimizing toxicity, this rapidly evolving field holds the promise of transforming the treatment of diseases like AMD and DME into safer, more convenient, and highly effective therapies.

Drug-Eluting Contact Lenses

Contact lenses offer a highly effective and patient-friendly method for sustained drug delivery to the anterior segment, largely by bypassing the rapid clearance caused by blinking and tear turnover. By providing close and continuous contact with the cornea, they ensure prolonged drug residence time, improved absorption, and controlled drug release, enhancing therapeutic outcomes and patient compliance. Researchers have engineered these lenses as drug reservoirs using techniques such as molecular imprinting (creating specific drug pockets) and integrating nanoparticle-laden layers into the lens matrix. The field has achieved a critical milestone with the regulatory approval of a lens for eye allergy relief, paving the way for future therapeutic lenses to treat chronic conditions such as glaucoma, dry eye, and to improve post-operative care.

Iontophoresis

Ocular Iontophoresis is an innovative, non-invasive drug delivery technique that uses a mild electric current to actively drive charged drug molecules (especially large or hydrophilic compounds) through ocular tissues such as the cornea and sclera. This electric field enhances drug penetration beyond the eye's natural barriers, allowing for rapid and controlled drug delivery. The key advantages include achieving increased drug concentrations in both the anterior and posterior segments, improving therapeutic efficacy, and reducing systemic side effects, ultimately offering a promising, non-invasive alternative to injections for various eye conditions

Microneedles

Microneedles are an emerging, minimally invasive drug delivery technology consisting of micron-scale projections designed to painlessly penetrate the eye's outer layers, primarily targeting the sclera to reach the posterior segment. They aim to overcome the risks of traditional intravitreal injections by bypassing key barriers such as the corneal epithelium and conjunctiva, thereby enhancing drug penetration and bioavailability. The two main types are hollow microneedles (which inject a solution) and solid microneedles (which are coated with a dissolving drug). Both types enable controlled, localized delivery with minimal discomfort and reduced risks of complications (e.g. from infection or retinal detachment), showing great promise in treating conditions such as age-related macular degeneration and diabetic retinopathy.

Gene Therapy

Gene therapy represents a revolutionary approach for treating inherited retinal diseases (IRDs), offering the potential for a one-time cure by using a safe carrier, typically an adeno-associated virus (AAV) vector, to deliver a healthy copy of a defective gene directly into retinal cells. The field was validated by the landmark 2017 approval of Luxturna® for a rare form of inherited blindness, confirming the eye's suitability for this therapy due to its immune-privileged status and accessibility. Building on this success, researchers are now actively exploring gene therapy for more widespread conditions such as age-related macular degeneration (AMD) and glaucoma.

Smart and Stimuli-Responsive Systems

The future of Ocular Drug Delivery Systems (ODDS) is focusing on developing "smart" systems capable of releasing drugs on-demand in response to specific biological triggers, thereby minimizing unnecessary drug exposure and side effects. For example, hydrogels or nanoparticles could be engineered to detect elevated levels of inflammatory enzymes (such as those present during a uveitis flare-up) and immediately release an anti-inflammatory drug only when and where it is needed. This targeted, responsive approach promises to enhance therapeutic efficacy, improve patient compliance by reducing dosing frequency, and usher in an era of personalized and precision ophthalmic treatment.

Conclusion

The field of ocular drug delivery has fundamentally shifted since 1999 from highly inefficient conventional eye drops (with <5% bioavailability) to a diverse array of advanced systems driven by materials science and nanotechnology. For the anterior segment, innovations focus on prolonged contact time through advanced mucoadhesives (such as thiolated polymers) and in situ gelling formulations (triggered by temperature or pH), alongside nanocarriers (nanoparticles, liposomes) for enhanced penetration. For the posterior segment, the major breakthrough is sustained-release intravitreal implants (both biodegradable and non-biodegradable), which have revolutionized the treatment of chronic conditions like AMD by providing months or years of stable drug levels. The future is being shaped by cutting-edge technologies, including drug-eluting contact lenses, iontophoresis, microneedles, and the potentially curative approach of gene therapy, all moving toward personalized, precise, and responsive therapies despite ongoing challenges in non-invasive posterior segment delivery.

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