Nasolachrymal drainage system
Nasolachrymal drainage system consists of three parts; the secretory system, the distributive system and the excretory system. The secretory portion is composed of the lacrimal gland that secreted tears are spread over the ocular surface by the eyelids during blinking. The secretory system is stimulated by blinking and temperature change due to the tear evaporation and reflux secretors that have an efferent parasympathetic nerve supply and secrete in response to physical and emotional stimulation e.g. crying. The distributive system consists of the eyelids and the tear meniscus around the lid edges of the open eye, which spread tears over the ocular surface by blinking, thus preventing dry areas from developing. The excretory part of the Nasolachrymal drainage system consists of the lachrymal puncta, the superior, inferior and common canaliculi; the lachrymal sac, and the nasochrymal duct. In humans, the two puncta are the openings of the lachrymal canaliculi and are situated on an elevated area known as the lachrymal papilla. It is thought that tears are largely absorbed by the mucous membrane that lines the ducts andthe lachrymal sac; only a small amount reaches the nasal passage [11,14].

Figure 2: Schematic diagram of naso-lachrymation drainage system

Tear film
The exposed part of the eye is covered by a thin fluid layer, the so-called precorneal tear film. The film thickness is reported to be about 3–10 Am depending on the measurement method used. The resident volume amounts to about 10μl. The osmolality of the tear film equals 310–350 mOsm/kg in normal eyes and is adjusted by the monovalent and divalent inorganic ions such as Na+, K+, Cl-, HCO3-, and proteins. The mean pH value of normal tears is about 7.4. Diurnal patterns of pH changes exist, with a general shift from acid to alkaline during the day. The buffer capacity of the tears is determined by bicarbonate ions, proteins, and mucins [16, 17]. Tears exhibit a non- Newtonian rheological behaviour. The viscosity is about 3 mPas [13]. The mean surface tension value is about 44 mN/m.

Ocular pharmacokinetics
The main routes of drug administration and elimination from the eye have been shown schematically in Fig. 3.

Fig. 3: Schematic presentation of the ocular structure with the routes of drug kinetics illustrated. The numbers refer to following processes: 1) transcorneal permeation from the lacrimal fluid into the anterior chamber, 2) non-corneal drug permeation across the conjunctiva and sclera into the anterior uvea, 3) drug distribution from the blood stream via blood-aqueous barrier into the anterior chamber, 4) elimination of drug from the anterior chamber by the aqueous humor turnover to the trabecular meshwork and Sclemm's canal, 5) drug elimination from the aqueous humor into the systemic circulation across the blood-aqueous barrier, 6) drug distribution from the blood into the posterior eye across the blood-retina barrier, 7) intravitreal drug administration, 8) drug elimination from the vitreous via posterior route across the blood-retina barrier, and 9) drug elimination from the vitreous via anterior route to the posterior chamber.

The barriers
Drug loss from the ocular surface
After instillation, the flow of lacrimal fluid removes instilled compounds from the surface of the eye. Even though the lacrimal turnover rate is only about 1 μl/min the excess volume of the instilled fluid is flown to the nasolacrimal duct rapidly in a couple of minutes [18]. Another source of non-productive drug removal is its systemic absorption instead of ocular absorption. Systemic absorption may take place either directly from the conjunctival sac via local blood capillaries or after the solution flow to the nasal cavity [19,20]. Anyway, most of small molecular weight drug dose is absorbed into systemic circulation rapidly in few minutes. This contrasts the low ocular bioavailability of less than 5% [18].
Drug absorption into the systemic circulation decreases the drug concentration in lacrimal fluid extensively. Therefore, constant drug release from solid delivery system to the tear fluid may lead only to ocular bioavailability of about 10%, since most of the drug is cleared by the local systemic absorption anyway [21].

Lacrimal fluid-eye barriers
Corneal epithelium limits drug absorption from the lacrimal fluid into the eye [22]. The corneal barrier is formed upon maturation of the epithelial cells. They migrate from the limbal region towards the centre of the cornea and to the apical surface. The most apical corneal epithelial cells form tight junctions that limit the paracellular drug permeation [23]. Therefore, lipophilic drugs have typically at least an order of magnitude higher permeability in the cornea than the hydrophilic drugs [24]. Despite the tightness of the corneal epithelial layer, transcorneal permeation is the main route of drug entrance from the lacrimal fluid to the aqueous humor (Fig. 3). In general, the conjunctiva is more leaky epithelium than the cornea and its surface area is also nearly 20 times greater than that of the cornea [25, 26]. Drug absorption across the bulbar conjunctiva has gained increasing attention recently, since conjunctiva is also fairly permeable to the hydrophilic and large molecules [27]. Therefore, it may serve as a route of absorption for larger bio-organic compounds such as proteins and peptides. Clinically used drugs are generally small and fairly lipophilic. Thus, the corneal route is currently dominating. In both membranes, cornea and conjunctiva, principles of passive diffusion have been extensively investigated, but the role of active transporters is only sparsely studied.

Blood-ocular barriers
The eye is protected from the xenobiotics in the blood stream by blood-ocular barriers. These barriers have two parts: blood-aqueous barrier and blood-retina barrier.
The anterior blood-eye barrier is composed of the endothelial cells in the uvea. This barrier prevents the access of plasma albumin into the aqueous humor, and limits also the access of hydrophilic drugs from plasma into the aqueous humor. Inflammation may disrupt the integrity of this barrier causing the unlimited drug distribution to the anterior chamber. In fact, the permeability of this barrier is poorly characterised. The posterior barrier between blood stream and eye is comprised of retinal pigment epithelium (RPE) and the tight walls of retinal capillaries [22,23]. Unlike retinal capillaries the vasculature of the choroid has extensive blood flow and leaky walls. Drugs easily gain access to the choroidal extravascular space, but thereafter distribution into the retina is limited by the RPE and retinal endothelia. Despite its high blood flow the choroidal blood flow constitutes only a minor fraction of the entire blood flow in the body. Therefore, without specific targeting systems only a minute fraction of the intravenous or oral drug dose gains access to the retina and choroid. Unlike blood brain barrier, the blood-eye barriers have not been characterised in terms of drug transporter and metabolic enzyme expression. From the pharmacokinetic perspective plenty of basic research is needed before the nature of blood-eye barriers is understood.

Corneal and Non-Corneal Routes of Absorption
Lacrimal drainage and systemic absorption from the conjunctiva can wash away ophthalmic drops which are the most common type of ocular drugs. This results in absorption of a small fraction of the drug. [28,29,30] For topical drugs, small lipophilic molecules are normally absorbed through the cornea, while large hydrophilic molecules such as proteins/gene based medicines are absorbed via the conjunctiva and sclera.[31] Of these routes, the mechanical and chemical barrier functions of the cornea control access of exogenous substances into the eye, thereby protecting intraocular tissues (Fig. 4).

The human cornea measures approximately 12 mm in diameter and 520 μm in thickness, and consists of five layers, including the epithelium, basement membrane (Bowman's layer), stroma, Descemet's membrane and endothelium (Fig. 3).

Figure 4: Corneal cellular organization, the cornea consists of various transport limiting layers. The tightest monolayer is made by outer superficial epithelial cells which display tight junction complexes. The wing and basal cells exhibit gap junctions. The stroma and Descemet’s membrane cover the inner endothelial cells which contain macula adherens and are more permeable.



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