Download Advances in Implants

The
Advances
and
Challenges
in
Ocular
Drug
EFFECT OF ENVIRONMENT AND CLOZAPINE ON BASAL AND
STIMULATED
MEDIAL
PREFRONTAL
GABA
RELEASE
IN
TWO
Delivery via Implantation Techniques
RAT
MODELS
OF
SCHIZOPHRENIA
Adedoyin Awodele, Faye Carrington, Alanna Cavanagh, Constance Gaya Cremers, Sarah Kileen, Melissa MacPherson..
Pharmacology, UCD School of Biomolecular and Biomedical Science, University College Dublin, Ireland.
Introduction
Why Implants?
•Provide sustained drug delivery to the posterior
or anterior segment of the eye
•Can be applied to various ocular layer depending
on disease: subconjuctival/intravitreal/intrasceral
•Implants reduce frequency of administration
compared to I.V. Route in relation to treating
diseases of the posterior segment, therefore they
reduce risk of SEs
Above: Insertion of Retisert
•Minimise the importance of patient compliance.
•Drug can be removed should toxicity occur.
Ocular drug barriers:
Dynamic:
Static:
•Tear Dilution- max. only 30µl tear
volume comfortably accomm. In eye
when the average eye drop is 50 µl in
volume – inevitable spillage!
•Naso-lacrimal duct- when tears
exceed normal tear volume of 7-10 µl
•Systemic Removal – the conjunctiva
is highly vascularised and any drug
permeating it is rapidly removed by
the
systemic
circulation
and
eventually transported to the GIT.
•Cornea-Hydrophobic and hydrophilic layers connected by
tight junctions and containing efflux pumps inducing
multidrug resistance. (p-glycoprotein and MRP)
•Sclera-Opaque matrix of proteoglycans and collagen that
acts as a filter with preferred permeability for small,
hydrophilic and positively charged molecules due to it’s
structure.
•Blood-Ocular Barriers –the blood-retinal barrier arises
from the retinal pigment epithelium prevents transfer of
molecules between itself and choroidal blood with tight
junctions and according to some studies show P-gp efflux
pumps present also.
Diseases of the Eye
•Age-related Macular Degeneration (AMD) : Damage to
retina by accumulation of drusen can cause loss of central
vision.
•Diabetic Retinopathy is a type of retinal damage that
can lead to blindness caused by microvascular changes
due to diabetes mellitus.
•Diabetic Macular Edema (DME) is the most common cause of
visual loss and is characterised by accumulation of extracellular
fluid in the macular which occurs after the break down of the
blood-retinal barrier due to dilated hyper-capillaries and microaneurysms..
•Glaucoma is caused by damage to the optic nerve by loss
of retinal ganglion cells and increased fluid pressure in the
eye.
What are they?
•.Usually made of polymers that release a drug over a
prolonged period of time. There are two types:
Implant Type:
Biodegradable
NonBiodegradable
Pros:
Cons:
No need for surgical
removal. Can be
fashioned into various
shapes. Increase halflife of drug.
Drug release can be
controlled more
precisely and for longer
periods of time (years.)
Control
of drug release from
degradable systems is
more difficult.
Must be surgically
removed. Larger
Incisions required for
insertion.
Non-Biodegradable
Retisert
Silicone cup
Top View
containing
drug
Release
orifice
•0.59mg tablet is held in
a silicone elastomer cup.
•The release orifice is
separated from the drug
by a PVA membrane.
•The structure is held
together with silicone
glue
3mm
Side View
2mm
5mm
PVA
structure
tab
•CMV Retinitis is a chronic, infection of the retina caused
by
the
cytomegalovirus.
Predominantly
affects
immunosuppressed individuals and estimated to affect 1540% of AIDS patients.
•Uveitis is the swelling and irritation of the uvea (anterior
segment) and can be caused by autoimmune disorders, infection
or exposure to toxins.
Vitrasert
•For treatment of chronic, non-infectious uveitis (inflammation) including
sympathetic ophthalmia.
•3mm x 2mm x 5mm in size
•Reservoir of flucinolone acetonide (corticosteroid thought to act by
inducing phospholipase A2 inhib. proteins). 600ng a day decreasing to 300400ng over the first month.
•Inserted through the pars plana into the vitreous humour
•Active for 2 and a half years
•Removal can cause problems
•SEs = Cataracts (observed in 90% of patients after 3 years), increased I.O
pressure, eye pain, headache, nasopharyngitis and joint pain.
Structure
•Retinitis Pigmentosa is a progressive retinal dystrophy which
affects the photoreceptors and causes loss of peripheral vision
and eventually central vision.
FDA approved in 1996, Vitrasert was first
non-biodegradable, intravitreal implant.
Used for the delivery of the anti-viral drug,
ganciclovir to treat AIDs-related
Cytomegalovirus (CMV) Retinitis.
Ganciclovir is a synthetic analogue of the
nucleoside 2-deoxyguanosine, which causes
chain termination, preventing replication.
Each implant holds 4.5-5mg of the prodrug
which is released at a rate of approx. 11.5µg/hr over 5-8 months.
The 4mm device consists of a compressed
drug pellet core which is completely
covered, except at its top surface, with the
impermeable polymer; EVA. This entire
assembly is then coated by the permeable
polymer; (PVA).
Pros: In addition, to reduced systemic S/Es, increased
efficacy and reduced dosing frequency, studies show
treatment with vitrasert significantly slows down the
median time to disease progression in comparison to I.V.
ganciclovir therapy.
Con: Increased risk of developing contralateral eye retinitis
and systemic CMV.
Surgical Implantation
The implant is inserted by making a 5-6mm scleral incision into the pars plana. It is
then fixed into place using sutures. The wound is closed and a saline solution is
injected to restore normal ocular pressure.
Most patients experience blurred vision which usually clears between 2-4 weeks
after surgery.
Implants: The way forward?
Side Effects and Complications
of Implants
Vitreous Haemorrhage
Endophthalimitis
Cystoid Macular Oedema
Retinal Detachment
Advances in Implants/ Developments
Injectable Implants:
•Iluvien is a non-biodegradable implant that was recently approved as a treatment for DME.
It is in phase II trials for the treatment of wet and dry AMD and RVO and its active
ingredient is fluocinolone acetonide. It can be delivered intravitreally using a 25 gauge
needle, this is a mninimally invasive procedure as there is no need for a suture and is easier
to deliver than retisert due to its smaller size.
Biodegradable
Ozurdex
Ozurdex is a biodegradable implant
that contains demaxethasone. It is an
intravitreal implant that delivers a
sustained release of demaxaethasone
(700ml) to the retina and vitreous
humour. Ozurdex can improve visual
acuity and macular thickness. It is used
to treat macular edema, retinal vein
occlusion and non-infectious uveitis
(posterior).
Encapsulated Cell Technology (ECT)
•ECT has been used in non-biodegradable implants and is a cell-based delivery system
whereby implants can be used to deliver genetically modified cells in a hollow tube made
from semi-permeable membrane with both ends of the polymer sealed. Ciliary
neurotrophic factor (CNTF) has been proved to protect the retina against degeneration.
An ETC implant containing NTC-201 cells which were human retinal pigment epithelial
cells that were modified to over produce CNTF were shown to significantly reduce
retinal degeneration in animal models.
Future Perspectives
References