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Florence Lorget, Steven Thomas Laing, Chris Schuetz, Isabella De Jong, Jeff Aaronson, Nardos Tassew; Intravitreal Administrations of pH 4.0-5.5 Vehicle Solutions are Well Tolerated in NZW rabbits. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2652. doi: https://doi.org/.
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Formulation development for intravitreally-administered drugs may necessitate the use of low pH solutions. Solutions of pH 5.5 – 7.4 have been previously administered intravitreally in preclinical studies and are well tolerated. However, the tolerability of pH solutions lower than 5.5 is unknown. The aim of this study is to characterize the ocular safety profile of pH solutions, ranging from 4.0-5.5 in 2 different formulation buffers, after a single intravitreal injection. The result from this study can inform formulation development on the tolerable pH ranges for intravitreal injection.
Twelve male New Zealand White rabbits were assigned to one of 5 groups and administered pH 4.0, 4.5, 5.0 (20 mM Acetate, 150 mM Sodium Chloride) and pH 5.0, 5.5 (20 mM Histidine Hydrochloride 150 mM Sodium Chloride) solutions, intravitreally. Each eye received 2x50μL injections 10-20 minutes apart. All solutions were isotonic. Clinical ophthalmic examinations, comprising both slit-lamp biomicroscopy and indirect ophthalmoscopy, and intraocular pressure (IOP) measurements were performed at pre-dose, on Day 1 before and after the first and second test article injections, and on Day 3 and 9. Survival checks, general health observations and detailed clinical observations were performed throughout the study. All animals were euthanized on Day 3 except 2 animals in pH 4 group, which were kept till Day 9. All eyes were collected for histopathological analysis.
All animals survived until their scheduled termination date. All ocular anomalies observed during in-life ophthalmic exams were procedure related and limited to slight ocular irritation, focal hyperemia, and/or increased retinal vascularization near the injection sites. There was no test article related in-life ocular inflammation or any microscopic finding at any tested pH or timepoint in histopathological assessment in any of the eyes. IOP values remained within the safe physiological range throughout the study. The test articles had no detrimental effect on body weight or any other clinical observation.
Vehicle solutions in the pH 5.5 - 7.4 range have been previously administered intravitreally and are well tolerated. The results from this study show that the tolerable pH range for intravitreal administration may be expanded to include pH 4.0 – 5.5 solutions.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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