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Janet Tully, Mari Yang, Stuart Williams, Sanjib Das, Rozemarijn S Verhoeven, RiLee Robeson, Rhett M Schiffman, Benjamin R Yerxa; In vitro and In vivo Sustained Release of Dexamethasone from Intravitreal Implants. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4111. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Intravitreal dexamethasone is used in the treatment of diabetic macular edema (DME), retinal vein occlusion (RVO), and uveitis. Here we demonstrate the ability to fabricate biodegradable, dexamethasone containing intravitreal implants that result in sustained release of dexamethasone in the rabbit for at least three months based on a predictive in vitro method.
Implants were analyzed for dexamethasone content by RP-HPLC. In vitro release rates were measured at 37C in several release media to correlate in vitro to in vivo release rates, 1X PBS, pH 7.4 with and without 0.1% triton X-100 and unbuffered saline. In vivo pharmacokinetics and duration were evaluated in albino rabbits. Rabbits were given an intravitreal injection of dexamethasone containing implants and concentrations of dexamethasone were determined by LC-MS/MS in the recovered implants and ocular tissues at day 7 and months 1 and 3.
Sustained release of dexamethasone was demonstrated in vitro and in the rabbit vitreous for greater than three months. When characterizing ENV formulations, both unbuffered saline and 1X PBS, pH 7.4 with 0.1% triton X-100 were predictive of overall duration in the rabbit. The day 7 and month 1 in vivo time points are underestimated with the non-surfactant containing release media. The 1X PBS, pH 7.4 with 0.1% triton X-100 is more predicative of the increased release in the rabbit at the earlier time points. However, saline was found to be the most predictive of Ozurdex ® duration in the rabbit, with 1X PBS, pH 7.4 with 0.1% triton X-100 overestimating the in vivo duration. (Figure 1).
Sustained release of dexamethasone from biodegradable, intravitreal implants was demonstrated in vitro and in the rabbit vitreous out to three months, with sustained concentrations of dexamethasone measured in rabbit ocular tissues. These results indicate that in vitro release is predictive of duration and can be predictive of release rates in the rabbit vitreous for formulation screening and development.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
Figure 1. Percent release of dexamethasone from ENV formulations (Groups A, B, and C) and Ozurdex (Group D) in different in vitro media and in rabbit vitreous.
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