Transcript OzurdexTM Sustained Dexamethasone Drug Delivery System

First approved pharmacotherapy for macular
edema following BRVO and CRVO
A
biodegradable dexamethasone implant
• Drug incorporated into polymer matrix
• Sustained medication release
• Polymer matrix gradually breaks down into inert
compounds
• Extruded form is implanted with an applicator – the
NOVADUR™ implant
 Self-sealing wound
•
Rod shaped tiny implant
•
0.45 mm in diameter and 6 mm in length
•
Contains 0.7mg of Dexamethasone (preservative free)
•
Novadur is a proprietary and innovative drug delivery
system (DDS).
•
Dexamethasone embedded in an inactive biodegradable
PLGA matrix. (60/40 drug/polymer)
Applicator and NOVADUR™ implant
Surface Release
Diffusion
Bulk Erosion
CH 3
O
O
Biodegradable Implant Gradually Transforms
Into Water and Carbon Dioxide
O
O
O
O
O
CH 3
CH 3
O
O
O
O
O
Sites of hydrolytic
cleavage during biodegradation
O
O
O
CH 3
O
Drug Release
Polymer Degradation
CH 3
Sites of hydrolytic cleavage during biodegradation
OH
HO
Drug Release O
Polymer
O Degradation
Lactic Acid
CH
Lactic
Acid
3
OH
HO
OH
HO
Glycolic Acid
Glycolic Acid
H2O, CO2, and natural metabolites
HO
OH
O
Water
and Carbon ODioxide
Lactic Acid
Before Implantation
After 3 Weeks

Implanted with 22-gauge applicator
• Through the pars plana

Wound is self-sealing
• No sutures required

Implant does not need to be sutured into
place
Retinal vein
occlusion
(RVO)1
Uveitis1
Inflammation
Neovascularisation
Vascular leakage
Wet age-related
macular degeneration
(wet AMD)2
1. Johnson MW. Am J Ophthalmol 2009;147:11–21;
2. Nowak JZ. Pharmacol Rep 2006;58:353–63.
Diabetic retinopathy (DR)/
diabetic macular edema (DME)1
Retinal disease
Vascular Disease


Diabetes
CRVO/ BRVO
Healthy Retinal
Microvessel
Inflammatory Mediator
 IL-1, 6, 8
 TNF-Alpha
VEGF
 Vasodilation
 Leukostasis
Primary Inflammatory
Disease
 Uveitis
 Diapedesis
 Permeability
Macular
Edema
 Inflammatory proteins

Corticosteroids inhibit the inflammatory response to a
variety of inciting agents.

They inhibit the edema formation, fibrin deposition,
capillary dilation, leukocyte migration, capillary
proliferation, deposition of collagen, and scar formation
associated with inflammation.

They stabilize endothelial cells tight junctions, inhibit the
synthesis of VEGF, prostaglandins & other key cytokines.

Arachidonic acid is released from membrane
phospholipids by phospholipase A2 .

It is postulated that lipocortins control the biosynthesis of
potent mediators of inflammation such as prostaglandins
and leukotrienes.

Corticosteroids are thought to act by the induction of
phospholipase A2 inhibitory proteins, collectively called
lipocortins.
Arachidonic acid
Corticosteroids
Phospholipase A2 .
Prostaglandins
Leukotrienes
lipocortins
Vascular Disease


Diabetes
CRVO/ BRVO
VEGF
 Vasodilation
 Leukostasis
Healthy Retinal
Microvessel
Primary Inflammatory
Disease
 Uveitis
Corticosteroids
 Diapedesis
 Permeability
Macular
Edema
Inflammatory Mediator
 IL-1
 TNF-Alpha
 Inflammatory proteins
Corticosteroid
Relative Potencies
Cortisone
Cortisol
0.8
1
Prednisone
4
Methylprednisolone
5
Triamcinolone
5
Betamethasone
25
Dexamethasone
Fluocinolone acetonide
25
25*
Table 59-2 Goodman & Gilman 9th Edition
*approximated from the literature
Fluorination at
9 position
increases
corticosteroid
receptor binding
 Desired
characteristics of an implantable
intravitreal drug delivery system
• Controlled, sustained drug release
• Simple insertion procedure
• Biodegradable implant (does not need to be
removed)
• Long-term safety