Ocular Implants – Vision For The Future

1. Ocular Implants – Vision For The Future A view on Why Implants are currently the most effective treatment for chronic diseases of the eye 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, Constance Gaya Cremers Pharmacology, UCD School of Biomolecular and Biomedical Science, University College Dublin, Ireland. Side View PVA structure tab Introduction 2mm Ocular drug barriers: Why Implants? Diseases of the Eye 5mm • Provide sustained drug delivery to the posterioror anterior segment of the eye. • Localised drug delivery, therefore reduced dose. • Can be applied to various ocular layers depending on disease: subconjuctival/intravitreal/intrasceral. • Implants reduce frequency of administration • and the risk of side effects. • Minimise the importance of patient compliance. • Age-related Macular Degeneration (AMD) : Damage to retina by accumulation of drusen can cause loss of central vision. http://en.wikipedia.org/wiki/Macular_degeneration • Diabetic Retinopathy is a type of retinal damage that can lead to blindness caused by microvascular changes due to diabetes mellitus. http://diabetestesting-578.com/warning-diabetic-peripheral-neuropathy • Diabetic Macular oedema (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 Ref: http://medgadget.com/2009/02/eye_implant_prevents_lost_vision.html What are they? http://od.pcli.com/articles/a-new-doctor/diabetes-and-cataract-surgery • 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: http://www.otm1.com/page/services_otm • Uveitis is the swelling and irritation of the uvea (anterior segment) and can be caused by autoimmune disorders, infection or exposure to toxins. http://www.medicinenet.com/script/main/art.asp?articlekey=121809 • 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. http://www.eyesite.ca/7modules/Module7/html/Mod7Case7Ref.html Ref: http://computerkiddoswiki.pbworks.com/w/page/16304712/Five%20Senses Implants. The way Forward? • Vitrasert • Retisert • 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). • For treatment of chronic, non-infectious uveitis (inflammation) including sympathetic ophthalmia. • 3mm x 2mm x 5mm in size • Reservoir of fluocinoloneacetonide (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 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. Side Effects and Complications of Implants Endophthalimitis http://www.primehealthchannel.com/endophthalmitis.html Vitreous Haemorrhage http://medweb.bham.ac.uk/easdec/vitreous_hemorrhage.html http://tpx.sagepub.com/content/36/1/49.full Structure • 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 Implants Vs. other Deliveries http://depts.washington.edu/hivaids/oit/case7/fig7d.html Cystoid Macular Oedema http://www.mvretina.com/education/12.html Retinal Detachment http://www.beltina.org/health-dictionary/retinal-detachment-symptoms-treatment-surgery-recovery.html Topical administration Pros: In addition, to having similar actions as other implants, 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 Ref: http://www.engagesite.com/healthwork.html Non-Biodegradable Implants Iluvien Ozurdex • Recently approved as a treatment for DME (Diabetic Macular Edema) • 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 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). Systemic administration IOVS- Investigative Ophthalmology & Visual Science (An ARVO Journal) Biodegradable Implant Ozurdex is made using a solid biodegradable polymer. This polymer is composed of an apolylactic acid-co-glycolic acid (PLGA) matrix. This dissolves completely in vivo. The products of this are lactic acid and glycolic acid, which are converted into Carbon dioxide and Water .http://www.psivida.com/products-iluvien.html 1.Iluvien ™ : a new sustained delivery technology for posterior eye disease Frances E Kane † , Judith Burdan , Antonio Cutino & Kenneth E.Green †Alimera Sciences, Inc. Intraocular Injections • 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 Above : Implant on day 3 (A) and day 180 (B) Conclusion Due to the physiology of the eye, ocular drug delivery poses a challenge. For this reason, routes which are favoured by patients for ease of administration are not the most effective forms of treatment. The bioavailability of drugs administered topically and systemically reaches a level which is far inferior to implant bioavailability. Intraocular injections also fall short of implants as they must be given every few weeks by a physician which is time consuming and unpleasant for patients. Until these issues are addressed or new less invasive techniques are developed, ocular implants appear to be the most favourable choice for chronic diseases of the eye. They are long lasting and eliminate patient compliance issues while bypassing many of the barriers which limit bioavailability of other administration routes. References: http://www.oculist.net/downaton502/prof/ebook/duanes/pages/v3/v3c028a.html, http://www.carolinaretinacenter.com/PE_article5.html, http://www.bausch.co.nz/en_US/ecp/pharma/product/vitrasert.aspx, "Ocular Drug Delivery" Authors : RipalGaudana, Hari Krishna Ananthula, AshwinParenky, and Ashim K. Mitra (http://www.helsinki.fi/farmasia/biofarmasia/opiskelu/provopinnot/bjktentti/ocular+PK.pdf) "THE CHALLENGES OF OPHTHALMIC DRUG DELIVERY: A REVIEW” AUTHORS: SINGH, AHMAD, HEMING (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895432/), Critical appraisal of the clinical utility of the dexamethasoneintravitreal implant (Ozurdex®) for the treatment of macular edema related to branch retinal vein occlusion or central retinal vein occlusion Annie Chan, Loh-Shan Leung, and Mark S Blumenkranz (Published online 2011 July 26), Dexamethasoneintravitreal implant for the treatment of noninfectious uveitis Rebecca S Hunter and Ann-Marie Lobo (published online 2011 November 11), http://www.bauschvrx.com/, http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/2010/01/WC500068245.pdf, Shalin, S et al. (2010). Drug delivery to the posterior segment of the eye for pharmacologic therapy. Expert Rev Ophthalmol.. 1 (5(1)), 75–93, Kompella, Uday B et al. (2010). Recent advances in ophthalmic drug delivery. Ther Deliv. 1 (3), 435-456, Short, Brian G. (2008). Safety Evaluation of Ocular Drug Delivery Formulations: Techniques and Practical Considerations. Toxicologic Pathology. 36 (49), 49-64.