REVIEW ON OCULAR DRUG DELIVERY

The human corneal epithelium is a stratified, squamous, non-keratinized epithelium 50 μm in thickness. It is composed of two to three layers of flattened superficial cells, wing cells, and a single layer of columnar basal cells which are separated by a 10–20 nm intercellular spaces and have regular intercommunications. These desmosome-attached cells can communicate via gap junctions through which small molecules traverse. Tight junctions (zonulae occludens) seal the superficial cells, building a diffusion barrier in the surface of the epithelium. Compared to the stroma and endothelium, the corneal epithelium represents a rate-limiting barrier which hinders permeation of hydrophilic drugs and macromolecules. The stroma displays hydrophilic nature due to an abundant content of hydrated collagen, which prevents diffusion of highly lipophilic agents. The corneal endothelial monolayer maintains an effective barrier between the stroma and aqueous humor. [32] Active ion and fluid transport mechanisms in the endothelium are responsible for maintaining corneal transparency. [33] It has been reported that certain drug properties such as lipophilicity, molecular weight, charge, and degree of ionization can significantly influence its passive permeability across the cornea. [34] Of these factors, lipophilicity plays a key role since transcellular permeation of lipophilic drugs through the cornea is faster and greater as compared to hydrophilic drugs. This route appears to be the main path for absorption of topical drugs. Greater molecular size decreases the rate of paracellular permeation of drugs. [35, 36] Once in the cornea, the drug can diffuse into the aqueous humor and the anterior segment (Fig. 3). However, local administration of conventional drugs via the corneal route fails to provide adequate concentrations within the vitreous and retina. [37,38] The conjunctiva is a mucous membrane consisting of vascularized epithelium (2-3 cell layers thick) and plays an important role as a protective barrier on the ocular surface since tight junctions are present on the apical surface of its cells. In fact, the bulbar conjunctiva represents the first barrier against permeation of topically applied drugs via the non-corneal route, which is the main intraocular route for entry of macromolecules and hydrophilic substances. Due to significant loss of drug through systemic circulation, the conjunctival sclera pathway appears to be a non-efficient path resulting in poor bioavailability. [39] The sclera is about 10 times more permeable than the cornea and half permeable as the conjunctiva. It is poorly vascularized and consists mainly of collagen and mucopolysaccharides, through which drugs can diffuse and enter the posterior segment (uveal tract, retina, choroid, vitreous humor).
Diffusion characteristics of various drugs were studied. Scleral permeability was significantly higher than that in cornea, and permeability coefficients of the beta-blockers ranked as follows: propranolol > penbutolol > timolol > nadolol for cornea, and penbutolol > propranolol > timolol > nadolol for the sclera.

Routes of ocular drug delivery
There are several possible routes of drug delivery into the ocular tissues (Fig. 3). The selection of the route of administration depends primarily on the target tissue. Traditionally topical ocular and subconjunctival administrations are used for anterior targets and intravitreal administration for posterior targets. Design of the dosage form can have big influence on the resulting drug concentrations and on the duration of drug action.

Topical ocular
Typically topical ocular drug administration is accomplished by eye drops, but they have only a short contact time on the eye surface. The contact, and thereby duration of drug action, can be prolonged by formulation design (e.g. gels, gelifying formulations, ointments, and inserts) [23]. During the short contact of drug on the corneal surface it partitions to the epithelium and in the case of lipophilic compounds it remains in the epithelium and is slowly released to the corneal stroma and further to the anterior chamber [40]. After eye drop administration the peak concentration in the anterior chamber is reached after 20–30 min, but this concentration is typically two orders of magnitude lower than the instilled concentration even for lipophilic compounds [21]. From the aqueous humor the drug has an easy access to the iris and ciliary body, where the drug may bind to melanin. Melanin bound drug may form a reservoir that is released gradually to the surrounding cells, thereby prolonging the drug activity. Distribution to the lens is much slower than the distribution to the uvea [22]. Unlike porous uvea, the lens is tightly packed protein rich structure where drug partitioning takes place slowly. Drug is eliminated from the aqueous humor by two main mechanisms: by aqueous turnover through the chamber angle and Sclemm's canal and by the venous blood flow of the anterior uvea [22] (Fig. 3). The first mechanism has a rate of about 3μl/min and this convective flow is independent of the drug. Elimination by the uveal blood flow, on the other hand, depends on the drug's ability to penetrate across the endothelial walls of the vessels. For this reason, clearance from the anterior chamber is faster for lipophilic than for hydrophilic drugs. Clearance of lipophilic drugs can be in the range of 20–30 μl/min. In those cases, most of drug elimination takes place via uveal blood flow. Halflifes of drugs in the anterior chamber are typically short, about an hour. The volumes of distribution are difficult to determine due to the slow equilibration of drug in the ocular tissues. The estimates in rabbits range from the volume of aqueous humor (250 μl) up to 2 ml [23]. In the latter case, the slow drug distribution to the vitreous is included in the volume of distribution. This distribution is slow, because the lens prohibits drug access to the vitreous. Flow of aqueous humor from the posterior chamber to the anterior chamber is another limiting factor. Some part of topically administered drugs may absorb across the bulbar conjunctiva to the sclera and further to the uvea and posterior segment (Fig. 3). This is an inefficient process, but may be improved by dosage forms that release drug constantly to the conjunctival surface. The role of this non-corneal route of absorption depends on the drug properties. Generally more hydrophilic and larger molecules may absorb via this route. They have particularly poor penetration across the cornea, and therefore, the relative contribution of the non-corneal is more eminent. Delivery across the conjunctiva and further to the posterior segment would be desirable, but unfortunately the penetration is clinically insignificant.

Sub-conjunctival administration.
Traditionally subconjunctival injections have been used to deliver drugs at increased levels to the uvea. Currently this mode of drug delivery has gained new momentum for various reasons. The progress in materials sciences and pharmaceutical formulation have provided new exciting possibilities to develop controlled release formulations to deliver drugs to the posterior segment and to guide the healing process after surgery (e.g. glaucoma surgery) [41]. Secondly, the development of new therapies for macular degeneration (antibodies, oligonucleotides) must be delivered to the retina and choroid [42, 43].
After subconjunctival injection drug must penetrate across sclera which is more permeable than the cornea. Interestingly the scleral permeability is not dependent on drug lipophilicity [44]. In this respect it clearly differs from the cornea and conjunctiva. Even more interesting is the surprisingly high permeability of sclera to the large molecules of even protein size [45]. Thus, it would seem feasible to deliver drugs across sclera to the choroid. However, delivery to the retina is more complicated, because in this case the drug must pass across the choroid and RPE. The role of blood flow is well characterise kinetically but the based on the existing information, there are good reasons to believe that drugs may be cleared significantly to the blood stream in the choroid. Pitkänen et al. showed recently that RPEis tighter barrier that sclera for the permeation of hydrophilic compounds [44]. In the case of small lipophilic drugs they have similar permeabilities. More complete understanding of the kinetics in sclera, choroid and RPE should help to develop medications with optimal activity in the selected posterior target tissues. Combination of the kinetic knowledge and cell selective targeting moieties offer very interesting possibilities.

Intravitreal administration.
Direct drug administration into the vitreous offers distinct advantage of more straightforward access to the vitreous and retina (Fig. 3). It should be noted, however, that delivery from the vitreous to the choroid is more complicated due to the hindrance by the RPE barrier. Small molecules are able to diffuse rapidly in the vitreous but the mobility of large molecules, particularly positively charged, is restricted [46]. Likewise, the mobility of the nanoparticles is highly dependent on the structure. In addition to the diffusive movement convection also plays a role [47]. The convection results from the eye movements.
After intravitreal injection the drug is eliminated by two main routes: anterior and posterior [22]. All compounds are able to use the anterior route. This means drug diffusion across the vitreous to the posterior chamber and, thereafter, elimination via aqueous turnover and uveal blood flow. Posterior elimination takes place by permeation across the posterior bloodeye barrier. This requires adequate passive permeability (i.e. small molecular size, lipophilicity) or active transport across these barriers. For these reasons, large molecular weight and water-solubility tend to prolong the half-life in the vitreous [22].
Drugs can be administered to the vitreous also in controlled release formulations (liposomes, microspheres, implants) to prolong the drug activity.

Mechanism of controlled sustained drug release into the eye
The corneal absorption represents the major mechanism of absorption for the most conventional ocular therapeutic entities.
Passive Diffusion is the major mechanism of absorption for nor?erodible ocular insert with dispersed drug. Controlled release can further regulated by gradual dissolution of solid dispersed drug within this matrix as a result of inward diffusion of aqueous solution.

Corneal barrier limitation for topically administered drug
The existing ocular drug delivery systems are thus fair and in-efficient. The design of ocular system is undergoing gradual transition from an empirical to rational basis; Interest in the broad areas of ocular drug delivery has increased in recent years due to an increased understanding of a number of ocular physiological process and pathological conditions. The focus of this review is the approaches made towards optimization of ocular delivery systems
1. Improving ocular contact time
2. Enhancing corneal permeability
3. Enhancing site specificity [48]

Ophthalmic drug product may be classified according to route of administration.
1. Topical
2. Intraocular
3. Systemic (oral and venous).
Absorption of drugs in the eye takes place either through corneal or non?corneal route.
Maximum absorption takes place though the cornea, which leads the drug into aqueous humor. Loss of the administered dose of drug, takes place through spillage and removal by the naso?lacrimal apparatus. The non corneal route involves the absorption across the sclera and conjunctiva into the intra ocular tissues.

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