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Stuart Williams, Rozemarijn S Verhoeven, Dustin Melton, Janet Tully, Sanjib Das, RiLee Robeson, Andres Garcia, Mari Yang, Benjamin R Yerxa; Nonclinical Development of An Intravitreal Extended Release Implant for the Treatment of Diabetic Macular Edema. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4457. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic macular edema (DME) is a leading cause of vision loss. Corticosteroid use in DME patients is effective but has been limited by available treatments. An extended release biodegradable IVT implant, which delivers a decreased dose of dexamethasone in a linear manner over approximately 6 months while still achieving efficacy, could reduce cataract and IOP elevation rates associated with current therapies.
ENV1105 was designed for intravitreal delivery using novel nano and microparticle PRINT technology to release dexamethasone with a near zero-order release rate over approximately 6 months. Drug content and in-vitro release were measured by RP-HPLC. In vitro release rates were measured at 37C in 1X PBS, pH 7.4 with 0.1% triton X-100. Pharmacokinetics and tolerability of ENV1105 or Ozurdex were assessed in the albino rabbit for up to 3 months post-dose. Ocular matrices, remaining implants, and plasma were processed and analyzed by LC-MS/MS, and rabbits were examined via slit lamp biomicroscopy and indirect ophthalmoscopy.
Extended release dexamethasone implants were fabricated with a high degree of mass and drug content uniformity and a low degree of implant to implant variability in drug release. In vitro data demonstrated a near zero-order release rate up to 6 months. For ENV1105, therapeutically relevant dexamethasone concentrations were present in target tissues of retina, choroid, and vitreous at all time points studied, while anterior and systemic exposure was not quantifiable. Posterior segment tissue concentrations following Ozurdex administration were generally not quantifiable at Month 3, and dexamethasone was quantifiable in aqueous humor and plasma through Month 1.
ENV1105 was developed with uniform size, shape, dose content, and a dexamethasone release profile of over 6 months. Intravitreal administration of a dose sparing, uniformly releasing dexamethasone implant produced extended delivery to the posterior target tissues with no quantifiable anterior or systemic exposure and excellent ocular tolerability, and may thus decrease the risk of adverse effects.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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