THE EFFECT OF A VISCOSITY AND AN ABSORPTION ENHANCER ON THE INTRA NASAL ABSORPTION OF METOPROLOL IN RATS

During this investigation metoprolol was used as a model drug to inves tigate the effect of formulation variables on the nasal absorption of a low dose of metoprolol. This was done firstly, to compare the bioava ilability of metoprolol after peroral administration with the bioavail ability found after intra nasal administration and secondly, to determ ine the influence of the incorporation of methyl cellulose as a viscos ity enhancing agent and polysorbate-80 as an absorption enhancer into various formulations, on the bioavailability of metoprolol. In order t o achieve the objectives the following metoprolol formulations were pr epared: formulations containing metoprolol in a sodium chloride soluti on (0.9% (w/v)) for nasal administration, as well as for per oral admi nistration, a formulation containing metoprolol in methyl cellulose (2 % (w/v)) only, and two formulations containing metoprolol in methyl ce llulose at two different concentrations (1% and 2% (w/v)) respectively , with the addition of polysorbate-80 (0.1% (w/v)) to both. A bioavail ability study was conducted in rats by determining the metoprolol plas ma concentrations at 0, 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, and 4 h after administration of the respective formulations. A HPLC method was used to determine the various plasma concentrations. The AUC values, used as an indication of bioavailability, showed that the bioavailability o f metoprolol was significantly improved after nasal administration (4. 1715 mu g/ml per h) compared to per oral administration (1.5648 mu g/m l per h). The inclusion of 2% methyl cellulose into the formula result ed in a further increase (AUC = 5.7930 mu g/ml per h) in the AUC compa red to both the previous mentioned formulas, probably due to an increa se in the contact time of the formulation with the nasal mucosa. The i nclusion of 0.1% polysorbate-80 concomitantly with the methylcellulose (2%) showed no statistically significant difference in the AUC values . In fact a decrease in the bioavailability was observed (AUC = 3.3087 mu g/ml per h) possibly due to drug entrapment in the presence of pol ysorbate. The bioavailability of the formulation containing methyl cel lulose (1%) and polysorbate-80 (0.1%) was equivalent to the formulatio n containing only 2% methyl cellulose. (C) 1998 Elsevier Science B.V. All rights reserved.