The Advances and Challenges in Ocular Drug Delivery via Implantation Techniques

1. The Advances and Challenges in Ocular Drug Delivery via Implantation Techniques Silicone cup containing drug EFFECT OF ENVIRONMENT AND CLOZAPINE ON BASAL AND STIMULATED MEDIAL PREFRONTAL GABA RELEASE IN TWO RAT MODELS OF SCHIZOPHRENIA Top View Release orifice 3mm AdedoyinAwodele, Faye Carrington, AlannaCavanagh, Sarah Kileen, Melissa MacPherson. Pharmacology, UCD School of Biomolecular and Biomedical Science, University College Dublin, Ireland. Side View PVA structure tab Introduction 2mm Why Implants? Ocular drug barriers: Diseases of the Eye 5mm • Provide sustained drug delivery to the posterioror anterior segment of the eye • Can be applied to various ocular layers 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 • Minimise the importance of patient compliance. • 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 micro-aneurysms.. Above: Insertion of Retisert What are they? • Glaucoma is caused by damage to the optic nerve by loss of retinal ganglion cells and increased fluid pressure in the eye. • .Usually made of polymers that release a drug over a prolonged period of time. There are two types: • Retinitis Pigmentosa is a progressive retinal dystrophy which affects the photoreceptors and causes loss of peripheral vision and eventually central vision. • CMV Retinitis is a chronic, infection of the retina caused by the cytomegalovirus. Predominantly affects immunosuppressed individuals and estimated to affect 15-40% 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. Implants Vs. Other Delivery • Retisert • Vitrasert • For treatment of chronic, non-infectious uveitis (inflammation) including sympathetic ophthalmia. • 3mm x 2mm x 5mm in size • Reservoir of flucinoloneacetonide (corticosteroid thought to act by inducing phospholipase A2 inhib. proteins). 600ng a day decreasing to 300-400ng over the first month. • Inserted through the pars plana into the vitreoushumour • 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. Side Effects and Complications of Implants • 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. 1-1.5µg/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). Structure Vitreous Haemorrhage Endophthalimitis • 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 Non-Biodegradable Implants Cystoid Macular Oedema Retinal Detachment • 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. Advances in Implants/ Developments Ozurdex Iluvien 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). • Recently approved as a treatment for DME • It weighs 0.18mg and dispenses 0.2µg of the drug daily • It is the only drug therapy for DME treatment • In phase II trials for the treatment of wet and dry AMD and RVO • Active ingredient is fluocinolone acetonide Future Perspectives Biodegradable Implants • DELIVERY • injected intra-vitreally using a 25 gauge needle. • minimally invasive procedure, no need for suture • Non-erodible insert • Designed to deliver drug for up to 3 years • Easier to deliver then retisert because of its smaller size References