Pharmaceutical Manufacturing Handbook: Production and

734 OCULAR DRUG DELIVERY
melanocytes exhibit blue, grey, or green, while many melanocytes are responsible
for the brown appearance of the iris. There is often a considerable quantitative difference
in drug response between light and heavily pigmented eyes [18] . The binding
of drugs with melanin can decrease the aqueous humor concentration of free drug
and is therefore likely to reduce the pharmacological response [19] .
Lens The lens is the transparent biconvex structure situated behind the iris and
in front of the vitreous. It plays an important role in the visual function of the eye
and also enables accommodation together with the ciliary muscle. The lens is made
up of slightly more than 30% protein (water - soluble crystallins) and therefore has
the highest protein content of all tissues in the body [20] . The lens receives its nutrients
from the aqueous humor and its transparency depends on the geometry of the
lens fi bres.
Blood – Ocular Barriers The blood – ocular barriers can be divided into the blood –
aqueous barrier and the blood – retinal barrier.
The blood – aqueous barrier is located in the anterior part of the eye and is formed
by the endothelial cells of the blood vessels in the iris and the nonpigmented cell
layer of the ciliary epithelium [21] . It regulates the solute exchange between the
blood and the intraocular fl uid, preventing unspecifi c passage of solutes that could
infl uence the transparency of the ocular tissues. The outward movement into the
systemic blood circulation is less restricted, allowing especially small and lipophilic
drug molecules to enter the uveal blood circulation [22] . These molecules are consequently
removed more rapidly from the anterior chamber than larger, hydrophilic
molecules, which are eliminated by the aqueous humor turnover only [23] .
The blood – retinal barrier can be found in the posterior part of the eye. It prevents
toxic molecules, plasma components, and water from entering the retina. It also
forms a barrier for passage of systemically administered drugs into the vitreous,
typically resulting in only 1 – 2% of the drug ’ s plasma concentration in the intraocular
tissues [24] .
5.9.2.2
Pharmacokinetic Considerations
After topical application of an ophthalmic solution, the solution is instantly mixed
with the tear fl uid and then spread over the eye surface. However, various precorneal
factors such as the drainage of the instilled solution, induced lacrimation,
normal tear turnover, noncorneal absorption, drug metabolism, and enzymatic degradation
limit the ocular absorption by shortening the contact time of the applied
drug with the corneal surface [25] . As a result, typically less than 10% of the instilled
dose is delivered into the intraocular tissues, whereas the rest is absorbed into the
systemic circulation, leading to various side effects [3, 25, 26] . A summary of the
drug deposition model in the eye after topical application as described by Lee and
Robinson [27] is given below.
Upon instillation, the topically applied drug solution is instantly diluted by the
resident tears, resulting in a signifi cant decrease in the concentration gradient
(driving force) and hence in the reduction of the transcorneal fl ux. Drainage of
lacrimal fl uid towards the nasolacrimal sac during blinking leads to a rapid elimination
of the ocular solution via the canaliculi.