Pharmaceutical Manufacturing Handbook: Production and

FORMULATION APPROACHES TO IMPROVE OCULAR BIOAVAILABILITY 749
formulations. Surfactants most frequently utilized for the preparation of MEs are
poloxamers, polysorbates, and polyethylene glycol derivatives [219] .
Similar to all other colloidal delivery systems discussed above it was hypothesized
by numerous research teams that a positive charge (provided by cationic surfactants
[220] ) would increase the ocular residence time of the formulation due to electrostatic
interactions with the negatively charged mucin residues. However, toxicological
studies contradicted this assumption regarding the ocular effects, and so far there
has been no publication demonstrating a distinct benefi cial effect of charged surfactants
incorporated into MEs.
Microemulsions can be classifi ed into three different types depending on their
microstructure: oil - in - water (o/w ME), water - in - oil (w/o ME), and bicontinuous ME.
They have been investigated by physical chemists since the 1940s but have only
gained attention as potential ocular drug delivery carriers within the last two
decades.
Gasco and co - workers [221] investigated the potential application of o/w lecithin
MEs for ocular administration of timolol, in which the drug was present as an ion
pair with octanoate. The ocular bioavailability of the timolol ion pair incorporated
into the ME was compared to that of an ion pair solution as well as a simple timolol
solution. Areas under the curve for the ME and the ion pair solution respectively
were 3.5 and 4.2 times higher than that of the simple timolol solution. A prolonged
absorption was achieved using the ME with detectable amounts of the drug still
present 120 min after instillation.
Various lecithin - based MEs were also characterized by Hasse and Keipert [131] .
The formulations were tested in terms of their physicochemical parameters (pH,
refractive index, osmolality, viscosity, and surface tension) and physiological compatibility
(HET - CAM and Draize test). In addition, in vitro and in vivo evaluations
were performed. The tested MEs showed favorable physicochemical parameters
and no ocular irritation as well as a prolonged pilocarpine release in vitro and in
vivo.
Muchtar and co - workers [129] prepared MEs with poloxamer 188 and
soybean lecithin to deliver indometacin to the ocular tissues. They found a threefold
increased indomethacin concentration in the cornea and aqueous humor 1 h
post - instillation.
Beilin et al. [222] demonstrated a prolonged ocular retention of a submicrometer
emulsion (SME) in the conjunctival sac using a fl uorescent marker (0.01% calcein)
as well as the miotic response of New Zealand Albino rabbits to pilocarpine. They
found that the fl uorescence intensity of calcein in SME was signifi cantly higher than
that of a calcein solution at all time points. Moreover, the pilocarpine SME exhibited
a longer duration of miosis than the simple pilocarpine solution. It should be mentioned
that SMEs are true emulsions, being different from MEs. They do not form
spontaneously and are kinetically rather than thermodynamically stable. They generally
require high - shear homogenization to form and are more susceptible to phase
inversion. Furthermore, they are neither transparent nor translucent but rather
turbid due their larger droplet size compared to MEs. While the two terms are used
interchangeably in the the scientifi c literature, they actually refer to two distinct
categories of dispersed systems and should be differentiated from each other.
The w/o MEs composed of water, Crodamol EO, Crill 1, and Crillet 4 were investigated
as potential ocular delivery systems by Alany et al. [133] . It was hypothesized