Transcleral drugs overcome usual delivery
WASHINGTON, DC - Transcleral drug delivery may lead to more effective
treatment of conditions affecting the retina and choroid, according
to a Research to
Prevent Blindness Foundation seminar.
Most of the current methods of delivering medications to the eye
cannot achieve sufficient concentrations in the retina or choroid.
It is crucial to be able to reach these structures with any potential
treatments for diseases such as age-related macular degeneration
(AMD) or diabetic retinopathy, Jayakrishna Ambati MD noted.
Dr Ambati described why the sclera is an attractive target for drug
delivery to the posterior segment of the eye. It has a large and
accessible surface as well as 75% to 80% hydration, making it conductive
for water soluble molecules. Since it is hypocellular, few proteolytic
enzymes or binding sites degrade or sequester drugs.
In in vitro tests with isolated scleras, Dr Ambati found that the
tissue was permeable to dextrans as large as 70 kD. Several antibodies
are in development to treat neovascular diseases and he found that
IgG (150 kD) also crossed the sclera.
Fortunately, scleral permeability does not decline much with age,
so treating chronic diseases and those affecting older people should
be feasible with transcleral drug delivery.
In experiments with rabbit sclera in vitro, permeability was inversely
related to molecular radius rather than molecular weight.
"Two molecules of the same weight but different shape move
differently. So, molecules which are spherical in shape can traverse
more than linear shaped molecules.
"Therefore, drug designers need to consider shape, not just
size, of molecules for transcleral delivery," Dr Ambati noted.
In vivo experiments demonstrated biologically relevant concentrations
of macromolecules in the retina and choroid after crossing the sclera.
In one experiment, Dr Ambati implanted an osmotic pump containing
antibodies under a rabbit's skin, ran a catheter to the eye and
sutured the tip to the surface of the sclera.
The antibodies were directed against VEGF (vascular endothelial
growth factor) action and inhibited the action of VEGF by 80% in
the choroid and by 70% in the retina. This system achieved therapeutic
levels in the choroid and retina for four weeks with negligible
The ratio of the concentration of the drug in the choroid to that
of the systemic circulation was several hundred fold, he said.
To obviate the need for an implantable pump, Dr Ambati turned to
MEMS (micro electromechanical systems) to fashion a tiny device
that can reside on the surface of the eye for extended periods and
deliver drugs on demand.
He described an experimental device made by ChipRx, Columbus, Ohio,
US which measures 8.0 mm x 6.0 mm x 4.0 mm.
The ability of the sclera to absorb and deliver drugs may be attributable
to its 'sponge-like' nature.
Bolus delivery into the subconjunctival space can overwhelm the
sclera's ability to absorb substances and the excess may end up
in the systemic circulation.
But gradual delivery via such a device appears to allow almost complete
absorption through the sclera.
The outer surface of the device is silicone rubber-like material.
Inside is a microchip with reservoirs of drugs.
An electrical current may dissolve a thin membrane, releasing the
drugs, or a current can cause a hydrogel to contract, releasing
drugs over a prolonged period - of the order of microlitres per
The flow rate is remotely programmable and would be adjusted according
to disease activity, for example.
"If the disease is better, you want to reduce the amount of
medication. If the disease is worse, you want to be able to up-modulate
it," Dr Ambati explained.
Transcleral delivery devices could overcome some of the limitations
of other drug delivery routes. Topical eye drops face a corneal
impermeability barrier, tearing, intraocular convection and a long
Systemically administered drugs may fail to reach sufficient concentrations
in the retina and choroid because of blood-ocular barriers. Furthermore,
systemic effects of these drugs may be hazardous, as in the case
of growth factors or their inhibitors.
Intravitreal polymer implants release drugs in a controlled fashion
over time (ganciclovir for cytomegalovirus retinitis, for example)
with minimal systemic drug levels.
However, they have several limitations, including complications
of ocular surgery, posterior dislocation, endophthalmitis, vitreous
haemorrhage and retinal detachment.
Such devices also have technical problems of a polymer permeability
limit for large molecules, the need for multiple implants for chronic
diseases and the retinal internal limiting membrane (ILM) barrier.
The ILM barrier prevents molecules larger than about 40 kD to 70
kD diffusing from the vitreous into the retina.
Dr Ambati predicts human trials of a delivery device which resides
on the surface of the eye will begin within two years.