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V. Andres-Guerrero, R. Herrero-Vanrell, A. Peral, J. Pintor, I. T. Molina-Martínez; Carboxymethyl Cellulose Enhances the Intraocular Hypotensive Effect of 5-MCA-NAT. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4066.
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Topical application of the melatonin analogue 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) produces a clear reduction of intraocular pressure (IOP). Carboxymethyl cellulose (CMC) and hydroxypropylmethyl cellulose (HPMC) are mucoadhesive polymers able to increase the ocular contact time of topical formulations.The aim of this work was to prepare new ophthalmic formulations of 5-MCA-NAT (100 µM) containing CMC (0.5%) of two different viscosities (CMC-1, 25-50 cps; CMC-2, 400-800 cps) and HPMC (0.3%) and evaluate the addition of these mucoadhesive polymers in the hypotensive effect of the active substance after instillation in rabbit eyes.
5-MCA-NAT (Tocris Bioscience, USA), CMC-1, CMC-2 and HPMC (Abarán Mat Primas, Spain). The polymers were dissolved in PBS (pH 7.4) isotonized with ClNa. In vitro cytotoxicity of the vehicles was evaluated by the MTT technique in human corneal limbal epithelial cells (HCLE, Schepens Eye Research Institute, USA) and human conjunctival cells (IOBA-NHC, Spain). Cells were exposed to formulacions during 15 minutes, 1 h and 4h. 25 µl of each formulation was instilled in the cul de sac of the rabbit eyes (Male New Zealand white rabbits 2.5-3Kg). As control, rabbits received the corresponding vehicle without 5-MCA-NAT. After instillation, IOP was measured once every hour for 8 hours.All the in-vivo experiments were conducted in compliance with the ARVO statements for the Use of Animals in Ophthalmolgy and Vision Research.
IOP time courses for formulations were studied (n=10). All the formulations were able to maintain the hypotensive effect up to 8 hours providing different maximal effects. The maximum IOP reduction was observed after the instillation of 5-MCA-NAT in CMC-2 0.5% (30.27% ±1.49). Taking the formulation of 5-MCA-NAT in PBS as a reference, significant differences in the maximal hypotensive effect were obtained between PBS (18.11% ±1.07), CMC-1(13.80% ±1.40) (p-value<0.05) and CMC-2 (30.27% ±1.49) (p-value<0.0001). No significant differences were found between PBS and HPMC 0.3% (15.68% ±1.20) (p-value=0.1521). The cytotoxicity assays demonstrated good tolerance for all the formulations (cell viability>80%).
The 5-MCA-NAT formulation containing medium viscosity CMC (CMC-2) is the most efficient reducing IOP when compared with PBS, CMC-1 and HPMC.
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