Development of an intranasal formulation containing indomethacin and xylometazoline for rhinosinusitis treatment.

Abstract

Use of the nasal route of drug administration dates back many years and is used both to achieve topical treatments and to allow systemic absorption. The objective was to develop a formulation with novel features which enhance prolonged contact with the nasal and sinusal lining, since this should increase any therapeutic benefit. The anti-inflammatory drug selected was indomethacin, which was combined with xylometazoline, an effective nasal decongestant agent. 28 Sprague-Dawley rats were used. They were then allocated at random to one of the four groups of equal size. All rats received a nasal application of 50mL of the platelet-activating factor solution at a concentration of 16 µg/mL and had induced rhinosinusitis. Indomethacin or xylometazoline HCl or both were dissolved in the oily phase of the solution and then a magnetic stirrer was used to homogenize the solution for 60 min at room temperature. All the O/W solutions exhibited stability and remained at neutral pH for the entire duration of the experiment. The only intervention was application of inactive 0.9% saline in group 1. The intervention was nasal application of xylometazoline and indomethacin in the combined formulation in group. The intervention was nasal application of xylometazoline only in group 3. The intervention was nasal application of indomethacin only in group 4. For the animals in group 1 (the controls), the mucosa had sustained a significant level of damage and the vessels were highly congested. Inflammatory cells were extensively infiltrating the mucosa. (Figure 1 - A1, 2, 3). In group 2, by contrast, the vessels were hardly congested and there were very few infiltrates. The epithelium appeared completely intact (Figure 1 - B1, 2, 3). Furthermore, when groups 1 and 2 were compared in terms of congested vessels, inflammatory cellular infiltrates and injury to the epithelium, the differences reached statistical significance, with p-values of <0.01, >0.001 and <0.001, respectively. Comparison of groups 2 and 4 with the control group also revealed statistically significant differences in terms of cellular infiltrates (p<0.001) and damage to the epithelium (p<0.001). For the degree of congestion of the vessels, however, the difference between groups was not at the level of statistical significance (p<0.071). Groups 3 and 4 differed at a statistically significant level in terms of degree of congested vessels, cellular infiltrates, and damage to the epithelium (p<0.025 and p<0.001). The sections from rats in groups 2 and 3 had a lower degree of congested vessels, which may be due to the actions of xylometazoline. In the future, topically applied intranasal NSAIDs will be valuable formulations. Innovative types of formulation, such as those demonstrating thixotropic behavior, permit the agent to remain in prolonged contact with the nasal and sinusal lining. Alongside increased efficacy, these preparations will also improve the side effect profile of NSAIDs, largely eliminating systemic effects.