The visual organ is one of the most critical sensory systems in the body. When treating ocular diseases, it is essential to adopt a holistic perspective, as systemic diseases or localized lesions far from the eye may contribute to ocular pathologies. Likewise, the treatment of eye diseases may have systemic implications. Due to the presence of anatomical barriers such as the blood-ocular barrier (including the blood-aqueous barrier and the blood-retinal barrier), localized drug administration is the mainstay of effective pharmacotherapy for most ocular diseases. Beyond strictly adhering to the indications for use, it is also crucial to understand the pharmacokinetics and pharmacodynamics of drugs in the ocular environment to ensure rational drug use.
Ocular Pharmacokinetics
The ability of a drug to achieve effective concentrations at its site of action within the eye and exert therapeutic effects depends on several factors: dosage, absorption rate, tissue-binding and distribution, drug circulation levels, inter-tissue transport, biotransformation, and excretion.
Drugs primarily enter intraocular tissues from the ocular surface through corneal transport. Initially, the drug distributes across the tear film, from where it transits the cornea, and subsequently reaches the eye’s interior. Both the epithelial and endothelial cell layers of the cornea are tightly bound, preventing passage of drugs through extracellular spaces, thus making drug transport across cell membranes necessary. Factors influencing corneal permeability include drug concentration, solubility, viscosity, lipophilicity, and surface activity. Higher drug concentrations and better solubility increase corneal permeability. Greater viscosity prolongs contact time with the cornea, thereby enhancing absorption. As the corneal epithelium and endothelium act as lipid barriers, while the tear film and corneal stroma are aqueous, drugs with both lipid- and water-soluble properties are ideal, though lipophilicity is more critical for penetrating the cornea. Surface-active substances in ophthalmic preparations can modify the corneal epithelial membrane’s barrier properties, thereby increasing drug permeability. Additionally, factors such as the pH and osmolarity of the drug are important—significant deviations from ocular physiological values may cause irritation and reflex tearing, consequently affecting drug absorption.
Drugs may also be absorbed through blood vessels within periocular structures, such as the limbal and conjunctival vasculature, and enter the eye via systemic circulation. Alternatively, drugs can diffuse directly into the eye through the conjunctiva, sclera, or orbital fascia. Once inside the eye, drugs predominantly diffuse through the aqueous humor to reach anterior segment tissues, while small amounts may diffuse through the vitreous to the surface of the retina. Some drugs act as prodrugs that are metabolized into active compounds during corneal transport, increasing bioavailability and reducing systemic side effects. Certain drugs follow the aqueous humor circulation pathway into systemic circulation before redistributing into various ocular tissues. After metabolism at their target sites, drugs are excreted either through the aqueous humor or through direct venous drainage.
Common Ophthalmic Dosage Forms and Administration Methods
Eye Drops
Eye drops are the most commonly used ophthalmic dosage form and are typically instilled into the lower conjunctival sac. Each drop generally contains 25–30 μl of fluid, while the conjunctival sac can hold a maximum of 10 μl of tear fluid. As a result, only a small portion of the medication remains within the conjunctival sac. For routine treatment, a single drop per application is sufficient. Under normal conditions, tear turnover replaces approximately 16% of the tear fluid per minute. Consequently, four minutes post-application, only 50% of the medicated solution remains in the tear film, and after ten minutes, only 17% persists. To enhance ocular absorption and minimize wastage, the minimum interval between successive eye drop applications should be at least five minutes. Applying gentle pressure to the nasolacrimal duct and closing the eyelids lightly for several minutes post-application can reduce drug drainage via the nasolacrimal pathway, increase ocular absorption, and decrease systemic side effects.
Eye Ointments
Eye ointments are used to enhance contact time between the medication and the ocular surface. Such ointments typically use yellow petroleum jelly, white lanolin, and colorless mineral oil as their bases, collectively known as grease ointments. These lipid-based bases significantly increase the absorption of lipophilic drugs in the eye. Water-soluble drugs in ointments exist as microcrystals, and only the medication dissolved at the surface of the ointment can mix with the tear film. This limits the concentration of water-soluble drugs in the tear film from reaching optimal therapeutic levels.
A major advantage of eye ointments is their ability to lubricate and cushion damaged areas of the ocular surface, such as corneal epithelial defects, thereby alleviating irritation symptoms. However, they can cause temporary blurring of vision, which is a notable drawback.
Periocular Injection
Periocular injection refers to the administration of drugs around the eye, including subconjunctival injection, sub-Tenon’s capsule injection (parabulbar injection), and retrobulbar injection. The common characteristic of these approaches is bypassing the corneal epithelium barrier to drug absorption. This method allows the administration of relatively large drug volumes (typically 0.5–1.0 ml), resulting in higher drug concentrations in the local ocular area, making it especially suitable for drugs with low lipophilicity. In subconjunctival injections, drug absorption primarily occurs through diffusion into the corneal stroma and limbal tissues, targeting the anterior segment. Sub-Tenon’s injection delivers drugs that penetrate the sclera, making it suitable for treating conditions of the iris and ciliary body. Retrobulbar injection enables therapeutic drug concentrations to reach the posterior segment and the optic nerve area, making it ideal for posterior segment diseases and optic nerve disorders. However, there is a risk of damaging extraocular orbital tissues or the globe during periocular injections.
Intraocular Injection
Intraocular injection involves administering drugs directly into the eye. Its primary advantage is the immediate delivery of effective drug concentrations to the target site. This method requires only small doses and concentrations of the drug, providing better efficacy. It is mainly used for treating intraocular inflammation, infections, vascular diseases, and for gene therapy in hereditary ocular disorders. Routes of administration include intracameral injection, intravitreal injection via the pars plana, suprachoroidal injection, subretinal injection, and drug delivery through infusion fluids during vitrectomy. Minimizing tissue damage is particularly critical during intraocular injection. Additionally, close attention is necessary to ensure that intraocular tissues tolerate the drugs well, minimizing toxic effects on ocular structures.
New Ophthalmic Drug Formulations
To enhance the bioavailability of eye drops, extend their duration of action in the local area, and reduce systemic absorption-related side effects, various formulations have been introduced. These include the addition of viscosity-enhancing excipients such as methylcellulose, sodium hyaluronate, polyvinyl alcohol, and polycarbophil to produce gel-form eye drops or in situ gel-forming eye drops that transition from liquid to gel upon application to the eye. Since drug concentrations in conventional eye drops fluctuate periodically between doses, often falling below therapeutic levels during trough phases, sustained-release drug delivery systems have been developed. These systems, made from polymers or high-molecular-weight compounds in film or particulate forms, or using nanoparticles and surface-functionalization technologies, enable controlled and prolonged release of drugs in the ocular environment. These systems maintain therapeutic drug concentration at a relatively stable level over an extended period, significantly reducing drug dosage, frequency, and adverse effects.
Collagen shields, resembling contact lenses, have been developed using biologically derived tissues to facilitate sustained drug release. Drugs can be integrated into the collagen in various proportions, absorbed through rehydration, or applied to the surface during wear. These shields provide a slow-release effect. Additionally, lipid microspheres, or liposomes, have been developed by using phospholipid molecules to form bilayer membranes with both hydrophobic and hydrophilic properties. This formulation enables both water-soluble and lipid-soluble drugs to be incorporated as carriers for ophthalmic drug delivery. Sustained-release devices and liposome formulations are especially suitable for intraocular drug delivery.
These new ophthalmic drug formulations offer convenient applications, prolonged therapeutic effects, and reduced adverse reactions, providing promising advancements for ophthalmic pharmacotherapy with vast potential for broader clinical use.