Pharmaceutical Manufacturing Handbook: Production and

FORMULATION APPROACHES TO IMPROVE OCULAR BIOAVAILABILITY 747
loaded with betaxolol. It seemed that the higher ocular activity was related to the
hydrophobic nature of the carrier and that the mechanism of action seemed to be
directly linked to the agglomeration of the particles in the conjunctival sac [1] . In
general, nanocapsules displayed a much better effect than nanospheres probably
due to the fact that the active compound was in its un - ionized form in the oily core
and could diffuse faster into the cornea. Diffusion of the drug from the oily core of
the nanocapsule to the corneal epithelium seems to be more effective than diffusion
from the internal, more hydrophilic matrix of the nanospheres [1, 209] .
In order to achieve a sustained drug release and a prolonged therapeutic activity,
nanoparticles must be retained in the cul - de - sac and the entrapped drug must be
released from the particles at a certain rate. If the release is too fast, there is no
sustained release effect. If it is too slow, the concentration of the drug in the tears
might be too low to achieve penetration into the ocular tissues [208] . The major
limiting issues for the development of nanoparticles include the control of particle
size and drug release rate as well as the formulation stability.
So far, there is only one microparticulate ocular delivery system on the market.
Betoptic S is obtained by binding of betaxolol to ion exchange resin particles. Betoptic
S 0.25% was found to be bioequivalent to the Betoptic 0.5% solution in lowering
the intraocular pressure [208] .
Liposomes Liposomes were fi rst reported by Bangham in the 1960s and have been
investigated as drug delivery systems for various routes ever since then. They offer
some promising features for ophthalmic drug delivery as they can be administered
as eye drops but will localize and maintain the pharmacological activity of the drug
at its site of action [1] . Due to the nature of the lipids used, conventional liposomes
are completely biodegradable, biocompatible, and relatively nontoxic [1] .
A liposome or so - called vesicle consists of one or more concentric spheres of
lipid bilayers separated by water compartments with a diameter ranging from 80 nm
to 100 μ m. Owing to their amphiphilic nature, liposomes can accommodate both
lipohilic (in the lipid bilayer) and hydrophilic (encapsulated in the central aqueous
compartment) drugs [207] . According to their size, liposomes are classifi ed as either
small unilamellar vesicles (SUVs) (10 – 100 nm) or large unilamellar vesicles (LUVs)
(100 – 300 nm). If more than one bilayer is present, they are referred to as multilamellar
vesicles (MLVs). Depending on their lipid composition, they can have a positive,
negative, or neutral surface charge.
Liposomes are potentially valuable as ocular drug delivery systems due to their
simplicity of preparation and versatility in physical characteristics. However, their
use is limited by instability (due to hydrolysis of the phospholipids), limited drug -
loading capacity, technical diffi culties in obtaining sterile preparations, and blurred
vision due to their size and opacity [42] .
In addition, liposomes are subject to the same rapid precorneal clearance as
conventional ocular solutions, especially the ones with a negative or no surface
charge [127] . Positively charged liposomes, on the other hand, were reported to
exhibit a prolonged precorneal retention due to electrostatic interactions with the
negative sialic acid residues of the mucin layer [2, 127, 208, 210 – 213] .
There have been several attempts to use liposomes in combination with other
newer formulation approaches, such as incorporating them into mucoadhesive gels
or coating them with mucoadhesive polymers [210] . Mucoadhesive polymers inves-