Development and Optimization of a Novel Lozenge Containing a Metronidazole-Peppermint Oil-Tranexamic Acid Self-Nanoemulsified Delivery System to Be Used after Dental Extraction: In Vitro Evaluation and In Vivo Appraisal

Abstract

In-depth studies on essential oil-based nanoemulsions (NEs) have centered on a variety of oral health issues. NEs improve the delivery of nonpolar active agents to sites and thereby boost the dissolution and distribution of the agents. Metronidazole-peppermint oil-tranexamic acid self-nanoemulsifying drug delivery systems (MZ-PO-TX-SNEDDS) were created and loaded into novel lozenges to act as antifungal, hemostatic, antimicrobial, and analgesic dosage forms after dental extractions. The design-of-experiments approach was used in creating them. To generate the NEs, different concentrations of MZ-PO (240, 180, and 120 mg), 2% TX (600, 450, and 300 mg), and S_mix1:1 (600, 400, and 200 mg) were used. The ideal formulation had serum levels of 1530 U/mL of interleukin-6, a minimal inhibitory concentration against bacteria of 1.5 µg/mL, a droplet size of 96 nm, and a blood coagulation time of 16.5 min. Moreover, the produced NE offered better MZ release. The adopted design was used to produce the ideal formulation; it contained 240 mg of MZ-PO, 600 mg of 2% TX, and 600 mg of S_mix1:1. It was incorporated into lozenges with acceptable characteristics and an improved capability for drug release. These lozenges had reasonable coagulation times, IL-6 serum levels, and MIC values. All of these characteristics are desirable for managing symptoms following tooth extractions. Therefore, these lozenges loaded with MZ-PO-TX-SNEDDs might be considered a beneficial paradigm for relieving complications encountered after tooth extractions.

Keywords: hemostatic; lozenges; metronidazole; nanoemulsion; optimization; peppermint oil; periodontitis; tooth extraction; tranexamic acid.

Figure 1

Chemical structure of metronidazole (A) and tranexamic acid (B).

Figure 2

The pseudoternary phase diagram of the MZ-PO phase, 2% TX-aqueous phase, and S_mix.

Figure 3

Measured solubility of MZ in different cosurfactants (means ± SD, n = 3).

Figure 4

Effects of different independent elements on the droplet size of various MZ-PO-TX-NEs as shown by (A) Perturbation plot, (B) contour plot, and (C) 3D surface plot showing the; effects of different independent elements on the blood coagulation time in rats after administration of various MZ-PO-TX-NEs as presented by (D) Perturbation plot, (E) contour plot, and (F) 3D surface diagram; The impacts of various independent factors on IL-6 serum levels in rats following the administration of various MZ-PO-TX-NEs as shown in the (G) perturbation, (H) contour, and (I) 3D surface diagrams; The influences of various explored parameters on MIC values following the use of various MZ-PO-TX-NEs are shown in the (J) perturbation, (K) contour, and (L) 3D surface diagrams.

Figure 5

In vitro release profiles of MZ from optimal NE and MZ aqueous dispersion.

Figure 6

In vitro release of MZ from different lozenges and the drug aqueous suspension.