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M.S. Spitzer, R.T. Kaczmarek, A. Sierra, E. Yoeruek, K.U. Bartz–Schmidt, P. Szurman; Sodium Hyaluronate Gel (Healon and Healon 5) as a Drug Release System for Hydrophilic Steroid Formulation in Ophthalmic Surgery: Release Kinetics and Antiproliferative Potential . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5127.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate the in vitro release kinetics, the safety and the antiproliferative potential of a concentrated hydrophilic steroid formulation from commercially available sodium hyaluronate gels (HA) used as a slow release system.
Dexamethasone and Healon (HA) or Healon 5 (HA5) were mixed preparing HA formulations containing dexamthasone in concentrations from 4 mg/ml to 20 mg/ml (7.7 mM to 38.7 mM). Non–cumulative and cumulative release into balanced salt solution or PBS as a receiver fluid was measured spectrophotometrically over 2 to 6 days. The release of the steroid was plotted as function of the square root of time. To assess the antiproliferative potential of HA containing dexamethasone monolayer cultures of human retinal pigment epithelium (ARPE19) and human tenon fibroblast (HTFB) cells were used
Cellular proliferative activity was monitored by BrdU–incorporation into cellular DNA. For cytotoxicity assays ARPE19 and HTFB cells were grown to confluence and then cultured in a serum–deficient medium to ensure a static milieu. MTT assay after one day and life/dead cell–mediated cytotoxicity kit after 6 days of incubation were used to exclude cytotoxicity.
The release kinetics from HA and HA 5 were identical – steady state was achieved after 48 hours in the non–cumulative measurements. 50% of the drug was released by 6 hours into BSS and PBS. The release rate slowed down after 24 hours. No kinetic differences were seen between the higher and the lower concentrations of dexamethasone. The release plotted as a function of the square root of time was consistent with a largely diffusion–controlled release system. Dexamethasone loaded HA showed a significant antiproliferative effect on ARPE19 and HTFB cells at dexamthasone concentrations of 0.9 mM or higher. No cytotoxicity could be seen after 1 and 6 days.
Dexamethasone loaded HA shows extended release of steroid over up to 2 days in concentrations high enough to inhibit proliferation of HTFB and RPE cells. Thus this formulation may be a valuable, easy to prepare adjunct for sustained antiproliferative drug effect in glaucoma surgery or other ophthalmic procedures.
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