Ocular drug delivery
Drugs are usually topically applied to the eyes in the form of drops or ointments for local action. Following topical administration, the drug is eliminated from the eye by nasolacrimal drainage, tear turnover, productive corneal absorption, and nonproductive conjunctival uptake.
There are two barriers to ocular drug adsorption: (a) the blood–aqueous barrier and (b) the blood–retina barrier. The blood–aqueous barrier is composed of the ciliary epithelium, the epithelium of the posterior surface of the iris, and blood vessels within the iris.
Drugs enter the aqueous humor at the ciliary epithelium and at blood vessels. Many substances are transported out of the vitreous humor at the retinal surface. The cornea and the conjunctiva are covered with a thin film, the tear film, which protects the cornea from dehydration and infection. For drugs administered through the topical route, the cornea is the main barrier to drug absorption. The cornea consists of three parts: the epithelium, the stroma, and the endothelium.
Both the endothelium and the epithelium have high lipid content and thus are penetrated by drugs in their unionized lipid-soluble forms. The stroma lying between these two structures has a high water content, and thus, drugs that have to negotiate the corneal barrier successfully must be both lipid soluble and water soluble to some extent.
Ocular drug absorption depends on both drug ionization and tear turnover. For example, the pH 5 solution induces more tear flow than the pH 8 solution, thus the concentration gradient is reduced, and transport of both ionized and nonionized drugs is less at pH 5. The duration of drug action in the eye can be extended by two approaches: (1) by reducing drainage using viscosity-enhancing agents, suspensions, emulsions, ointments, and polymeric matrices and (2) by improving corneal drug penetration using ionophores and liposomes.
Prodrug derivatization can be employed to overcome low corneal permeability of water-soluble drugs. The drug molecules can be chemically modified to obtain suitable structural configuration and physicochemical properties to afford maximal corneal adsorption. However, a prodrug must be converted enzymatically or chemically to the parent drug in vivo to elicit its effect. Choline esterases, which are abundant in the corneal epithelium, can be used for delivery of more lipophilic esterified prodrugs of watersoluble compounds to the eye.
Routes of drug administration into the eye
Topical route of drug administration: Treatment of anterior segment diseases usually utilizes topical route of drug administration. This route presents challenges such as precorneal tear clearance, limited conjunctival drug absorption, metabolism by the iris-ciliary body, and elimination through the canal of Schlemm.
Systemic drug administration: Systemic drug administration is usually not preferred for drug delivery to the eye. However, in certain cases, such as the treatment of glaucoma, administration of drugs, such as acetazolamide, through the systemic route may be preferred to obviate the drug absorption limitation due to high intraocular pressure.
Intravitreal administration: Intravitreal (IVT) injection is utilized for the treatment of posterior segment diseases, for example, diabetic retinopathy, and viral infections, for example, human cytomegalovirus (HCMV) retinitis and endophthalmitis. Direct administration to the vitreous humor overcomes the blood-retinal barrier (BRB). This route, however, requires injections in the eye and may cause retinal detachment, which could lead to vision loss. Thus, prolonged drug release strategies, including prodrugs, have been utilized to prolong drug residence time in the vitreous humor.
Periocular administration: The periocular route of administration provides direct access to the sclera, and can result in high drug concentration both in the anterior and posterior segments of the eye. The periocular drug injections could be retrobulbar, peribulbar, subtenon, and subconjunctival, depending on the site of injection.
Retrobulbar injection: Direct injection into the retrobulbar space can be useful for drug delivery into the macular region (highly pigmented yellow spot near the center of retina, rich in ganglion cells and responsible for central vision). This injection can, however, result in damage to the blood vessels.
Peribulbar injection: The peribulbar injection can be c ircumocular, periocular, periconal, or apical depending on the exact site of injection. This route is generally utilized for the administration of analgesics.
Subtenon injection: This site of drug injection can be utilized for drug delivery to the posterior segment of the eye. The drug is administered into the tenon space, which is formed by the void between the tenon’s capsule and the sclera.
Subconjunctival injection: This periocular route of drug administration can allow up to 500 μL of drug solution to be injected. This route is utilized for the treatment of both anterior and posterior segment diseases.
Challenges to ocular drug delivery
Topically administered drugs can be eliminated via precorneal tear clearance, blinking, and nasolacrimal drainage. This presents challenges to the entry of drug molecules to the anterior segment of the eye. Drug delivery to the posterior segment of the eye is challenged by barriers such as inner and outer BRBs and efflux pumps. In addition, the presence of efflux pumps, such as P-glycoprotein (P-gp), multidrug resistance associated proteins (MRPs), and breast cancer resistant protein, also limits the ocular bioavailability of drugs.
For drugs administered through the topical route, the cornea is the main barrier to drug absorption. The cornea and the conjunctiva are covered with a thin film, the tear film, which protects the cornea from dehydration and infection. Following topical administration, a drug is eliminated from the eye by nasolacrimal drainage, tear turnover, productive corneal absorption. and nonproductive conjunctival uptake. The cornea has three anatomical parts: (1) the epithelium, (2) the stroma, and (3) the endothelium.
Both the endothelium and the epithelium have high lipid content, and thus are penetrated by drugs in their unionized lipid-soluble forms. The stroma lying between these two structures has high water content. To penetrate the cornea, drugs have to go through both the lipidic and aqueous anatomical components.
For drugs injected into the eye, there are two main barriers to ocular drug adsorption: (a) the blood-aqueous barrier and (b) the blood-retina barrier. The blood-aqueous barrier is composed of the ciliary epithelium, the epithelium of the posterior surface of the iris, and blood vessels within the iris. Drugs enter the aqueous humor at the ciliary epithelium and in the blood vessels. Many substances are transported out of the vitreous humor at the retinal surface.