Pharmaceutical Manufacturing Handbook: Production and

1348 OIL-IN-WATER NANOSIZED EMULSIONS
noncorneal route and appeared to enter certain intraocular tissues through the
conjunctiva/sclera [148 – 150] . Indeed when compared to the cornea, drug penetration
through the conjunctiva has the advantage of a larger surface area and higher
permeability, at least for drugs which are not highly lipophilic. Furthermore, the
lasting presence of drug molecules in the lower conjunctival cul - de - sac of the eye
could result in a reservoir effect. Nevertheless, the o/w nanosized emulsions more
or less physically resemble a simple aqueous - based eye drop dosage form since
more than 90% of the external phase is aqueous irrespective of the formulation
composition. Hence, following topical administration, nanosized emulsions would
probably face almost similar ocular protective events as encountered with conventional
eye drops into the eye. The o/w nanosized emulsions are likely to be destabilized
by the tear fl uid electrolytic and dynamic action. Because of constant eyelid
movements, the basal tear fl ow rate (1.2 μ L/min), and the refl ex secretion induced
by instillation (up to 400 μ L/min depending on the irritating power of the topical
ocular solutions [35] ), topical eye drop dosage forms are known for being rapidly
washed out from the eye. Therefore, the water phase of the emulsion is drained off
while, probably, the oil phase of the emulsion remains in the cul - de - sac for a long
period of time and functions as a drug reservoir [35] . If the volume of instilled emulsion
in the eye exceeds the normal lachrymal volume of 7 – 10 μ L, then the portion
of the instilled emulsion (one or two drops, corresponding to 50 – 100 μ L) that is not
eliminated by spillage from the palpebral fi ssure of conjunctiva is drained quickly
via the nasolacrimal system into the nasopharynx. In other words, the larger the
instilled volume, the more rapidly the instilled emulsion is drained from the precorneal
area. Hence the contact time of the emulsion with the absorbing surfaces
(cornea and conjunctiva) is estimated to be a maximum of a few minutes, well
beyond the short residence time of conventional eye drops. In order to verify the
extension of the residence time of the emulsion in the conjunctival sac, Beilin et al.
[151] added a fl uorescent marker to the formulations. One minute after the topical
instillation into eye, 39.9 ± 10.2% of the fl uorescence was measured for the nanosized
emulsions whereas only 6.8 ± 1.8% for regular eye drops. In addition a study
was carried out in male albino rabbits to compare the corneal penetration of indomethacin
from Indocollyre (a marketed hydro - PEG ocular solution) to that of
negatively and positively charged emulsions [108] . By this comparison, it was
intended to gain insightful mechanistic comprehension regarding the enhanced
ocular penetration effect of the emulsion as a function of dosage form and surface
charge. The contact angle of one droplet of the different dosage forms on the cornea
was measured and found to be 70 ° for saline, 38 ° for the anionic emulsion, and 21.2 °
for the cationic emulsion. Respectively, the values of the calculated spreading coeffi
cient were − 47, − 8.6, and − 2.4 mN/m. It can clearly be deduced, owing to the
marked low spreading coeffi cient values elicited by the emulsions, that both nanosized
emulsions had better wettability properties on the cornea compared to saline.
The emulsion may then prolong the residence time of the drop on the epithelial
layer of the cornea, thereby enabling better drug penetration through the cornea to
the internal tissues of the eye, as confi rmed by animal studies [108] . It is therefore
believed that drug is not released from the oil droplet and equilibrates with the
tears but rather partitions directly from the oil droplets to the cell membranes on
the eye surface. Therefore, it is reasonable to consider that nanosized emulsions
have a real advantage since they elicit an increased ocular residence time in com-