OzurdexTM Sustained Dexamethasone Drug Delivery System

Sustained Dexamethasone Drug Delivery System

First approved pharmacotherapy for macular edema following BRVO and CRVOOzurdex and Novadur ImplantDr. Bharti KashyapKashyap Memorial Eye Hospital1

A biodegradable dexamethasone implantDrug incorporated into polymer matrixSustained medication release Polymer matrix gradually breaks down into inert compounds Extruded form is implanted with an applicator the NOVADUR implantSelf-sealing wound2 NOVADUR implantRod 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)

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Applicator and NOVADUR implant4Drug Release From Biodegradable Implants Three Phases of ReleaseSurface Release5DiffusionDrug Release From Biodegradable Implants Three Phases of Release6Bulk ErosionDrug Release From Biodegradable Implants Three Phases of Release7Drug Delivery TechnologyBiodegradable Implant Gradually Transforms Into Water and Carbon Dioxide

Lactic AcidGlycolic AcidWater and Carbon Dioxide8The polymer matrix that carries the drug is gradually metabolized into inert components.Small amounts of lactic and glycolic acid appear transiently before being broken down into water and carbon dioxide.Changes in Polymer Matrix Over Time

After 3 Weeks

Before Implantation9These figures illustrate how the polymer matrix breaks down over time.Implanted with 22-gauge applicatorThrough the pars planaWound is self-sealingNo sutures requiredImplant does not need to be sutured into place10The implantation of the extruded form of Posurdex can be an office-based procedure.A 22-guage applicator is used that produces a small, self-sealing wound.

Retinal vein occlusion (RVO)1Inflammation: a key component in the pathogenesis of retinal disease1,2Wet age-related macular degeneration (wet AMD)2Diabetic retinopathy (DR)/diabetic macular edema (DME)1InflammationNeovascularisationVascular leakageRetinal diseaseUveitis1 Johnson MW. Am J Ophthalmol 2009;147:1121; Nowak JZ. Pharmacol Rep 2006;58:35363. The pathogenesis of retinal disease is multifactorial and involves the processes of inflammation, vascular leakage and neovascularisation [1-2]ME as a consequence of retinal disease is a leading cause of vision loss, and therefore has an important medical and socioeconomic importance [1]

References[1] Johnson, 2009[2] Nowak, 2006

Macular EdemaPathophysiology Corticosteroid-Based Therapies Vasodilation Leukostasis Diapedesis Permeability Inflammatory proteins Primary Inflammatory DiseaseUveitis Inflammatory MediatorIL-1, 6, 8TNF-Alpha

Healthy Retinal MicrovesselVEGFVascular Disease DiabetesCRVO/ BRVO12Corticosteroid-Based TherapiesCorticosteroids 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.13Corticosteroid-Based TherapiesArachidonic 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.

14 Arachidonic acid Corticosteroids Phospholipase A2 . Prostaglandins Leukotrienes lipocortins15

Macular Edema

Healthy Retinal MicrovesselPathophysiology Corticosteroid-Based TherapiesVEGF Vasodilation Leukostasis Diapedesis Permeability Inflammatory proteinsVascular Disease DiabetesCRVO/ BRVO Primary Inflammatory DiseaseUveitis Inflammatory MediatorIL-1TNF-AlphaCorticosteroidsCorticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation.There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2 .

16Table 59-2 Goodman & Gilman 9th Edition*approximated from the literatureRelative Potencies of CorticosteroidsCorticosteroidRelative PotenciesCortisone0.8Cortisol1Prednisone4Methylprednisolone5Triamcinolone5Fluorination at 9 position increases corticosteroid receptor bindingBetamethasone25Dexamethasone25Fluocinolone acetonide 25*17This table lists the relative potencies of several corticosteroids and it shows that not all steroids are created equal. The superior potency of the synthetic corticosteroids is due to fluorination at the 9-alpha position, which increases the receptor binding affinity. In comparison with cortisol, an equal weight of triamcinolone has 5 times the potency, and an equal amount of dexamethasone has 25 times the potency.

Reference Goodman & Gilman's The Pharmacological Basis of Therapeutics, 10th Edition. Hardman JG, Limbird LE, Gilman AG (eds.). McGraw-Hill Professional.

Desired characteristics of an implantable intravitreal drug delivery system Controlled, sustained drug releaseSimple insertion procedure Biodegradable implant (does not need to be removed)Long-term safety18The ideal implantable intravitreal drug delivery system should deliver a controlled amount of the desired drug for a long period of time.It should be simple to insert and be biodegradable so that it never has to be removed. It should also have good long-term safety.Thank You19