Pharmaceutical Manufacturing Handbook: Production and

MEDICAL APPLICATIONS OF OIL-IN-WATER NANOSIZED EMULSIONS 1351
comparison to eye drops. Anselem et al. [161] and Melamed et al. [162] prepared a
nanosized emulsion containing adaprolol maleate, a novel soft β - blocking agent, and
observed a delayed IOP depressant effect in human volunteers. A similar pharmacological
effect was also observed in human volunteers by Aviv et al. [163] using
pilocarpine base - loaded emulsion. Another randomized human trial conducted by
Garty et al. [164] compared the activity of the pilocarpine base - laden nanosized
emulsion instilled twice daily with a generic dosage form instilled four times a day
to 40 hypertensive patients for seven days. No local side effects were observed. The
IOP decreased 25% in both formulations during this time period. No signifi cant
difference was noticed between the two treatments. These results proved that the
anionic emulsion extended the action of the drug and two daily administrations have
the same result as four instillations of regular eye drops.
A novel nanosized anionic emulsion incorporating the immunomodulatory agent
cyclosporin A was developed and the clinical effi cacy was investigated for the treatment
of moderate to severe dry - eye disease in humans [165 – 167] . The novel cyclosporin
A ophthalmic dosage form represents a real breakthrough in the formulation
of a complex, highly lipophilic molecule such as cyclosporin A within an o/w nanosized
emulsion. Following thorough validation of this formulation through several
clinical studies in various countries [165 – 175] , an anionic o/w emulsion containing
cyclosporin A 0.05% (Restasis, Allergan, Irvine, CA) was approved for the fi rst time
by the FDA, on December 23, 2002. In addition, this anionic emulsion having cyclosporin
A is now available at pharmacies in the United States for the treatment of
chronic dry - eye disease (available at www.restasis.com and www.dryeye.com ). Furthermore,
an over - the - counter (OTC) product that features an emulsion formula,
Refresh Endura, is already launched in the U.S. market for eye - lubricating purposes
in patients suffering from moderate to severe dry - eye syndrome.
The effect of Restasis on contact lens comfort and reducing dry - eye symptoms
in patients with contact lens intolerance was evaluated in comparison to rewetting
drops (carboxymethylcellulose 0.5%, Refresh Contacts) [176] . Both formulations
were applied twice per day before and after lens wear. Symptoms were assessed by
lens wear time, use of rewetting drops during lens wear, subjective evaluation of
dryness, and completion of the ocular surface disease index questionnaire. The
results of this pilot study indicate that cyclosporin 0.05% is benefi cial for contact
lens wearers with dry eye and reduces contact lens intolerance [176] . Furthermore,
Sall et al. [177] have recently evaluated the effi cacy of marketed artifi cial tears
(Systane and Restasis) in relieving the signs and symptoms of dry eye when used
as supportive therapy to a cyclosporin - based ophthalmic emulsion (i.e., Restasis +
Systane vs. Restasis + Refresh). Signifi cant differences were seen in favor of Restasis
+ Systane versus Restasis + Refresh for less ocular burning, stinging, grittiness, and
dryness. Systane was better than Restasis + Refresh for less burning, dryness, and
scratchiness. Results indicate that the choice of concomitant therapy used with
Restasis has signifi cant effects on outcome measures and both supportive therapies
were compatible with Restasis [177] .
When compared to either saline or anionic emulsions, the nanosized cationic
emulsions were shown to enhance the ocular bioavailability of indomethacin [108] ,
piroxicam [178] , and cyclosporin A [106, 179] following one single - drop dose instillation
into the rabbit eye (Figure 4 ). A signifi cant drug reservoir effect was noted
in the cornea and conjunctiva even for more than 8 h following the instillation [106] .