Pharmaceutical Manufacturing Handbook: Production and

FORMULATION APPROACHES TO IMPROVE OCULAR BIOAVAILABILITY 751
side effects. Wei et al. [135] compared the ocular penetration, distribution, and
metabolism of epinephrine and dipivalyl epinephrine and found the partition coeffi
cient of the later to be 100 – 600 times higher than that of epinephrine, therefore
leading to a 10 - times faster absorption into the rabbit eye.
Dipivefrin was the only commercially available ophthalmic prodrug at that time.
However, numerous prodrug derivates have been designed to improve the effi cacy
of ophthalmic drugs ever since.
Jarvinen and co - workers [136] synthesized unique O, O′ - (xylylene)bispilocarpic
acid esters containing two pilocarpic acid monoesters linked with one moiety. The
found that prodrug showed a two - to seven - fold higher corneal permeability than
pilocarpine itself despite the high molecular weight.
Tirucherai et al. [137] formulated an acyl ester prodrug of ganciclovir. The
increased permeability was associated with a linear increased susceptibility of the
ganciclovir esters to the esterases present in the cornea.
So far, aims that have been achieved by using prodrugs include the modifi cation
of the drug ’ s duration of action, reduction of the systemic absorption, and reduction
of ocular and systemic side effects. Although prodrugs are commonly used to treat
diseases of the anterior segment, there have also been attempts to treat conditions
associated with the posterior segment of the eye.
Penetration Enhancers The transport process across the corneal tissue is the rate -
limiting step in ocular drug absorption. Increasing the permeability of the corneal
epithelium by penetration enhancers is likely to enhance the drug transport across
the corneal tissues and therefore improve ocular bioavailability of the drug.
Penetration enhancers act by increasing the permeability of the corneal cell
membrane and/or loosening the tight junctions between the epithelial cells, which
primarily restrict the entry of molecules via the paracellular pathway. Classes of
penetration enhancers include surfactants, bile salts, calcium chelators, preservatives,
fatty acids, and some glycosides such a saponin.
Surfactants are perceived to enhance drug absorption by disturbing the integrity
of the plasma membranes. When present at low concentrations, surfactants are
incorporated into the lipid bilayer, leading to polar defects in the membrane, which
change the membrane ’ s physical properties. When the lipid bilayer is saturated,
micelles start to form, enclosing phospholipids from the membranes, hence leading
to membrane solubilization [36] . Saettone et al. [138] found an increased corneal
permeability for atenolol, timolol, and betaxolol by including 0.05% Brij 35, Brij 78,
and Brij 98 into their formulations.
Bile salts are amphiphilic molecules that are surface active and self - associate to
form micelles in aqueous solution. They increase corneal permeability by changing
the rheological properties of the bilayer [231] . A number of bile salts such as deoxycholate,
taurodeoxycholate, and glycocholate have been tested so far, and it was
suggested, that a difference in their physicochemical properties (solubilizing activity,
lipophilicity, Ca 2+ sequestration capacity) is probably related to their performance
as permeability - enhancing agents [36] .
Another class of penetration enhancers includes calcium chelators such as ethylenediaminetetraacetic
acid (EDTA). These molecules induce Ca 2+ depletion in the
cells. This leads to a global change within the cell and as a result loosens the tight
junctions between superfi cial epithelial cells, thus facilitating paracellular transport