(T1130-09-57) Enhanced Topical Delivery of Metronidazole: A Comparative Study of Single and Binary Solvent Systems

Purpose: Although various topical formulations of metronidazole are available for treating rosacea, their skin permeation efficiency is often limited, which may reduce therapeutic effectiveness. Selection and appropriate combinations of solvents offers one possibility for enhancement of topical skin delivery of actives. To optimize skin delivery of metronidazole, this study aimed to compare the in vitro permeation of metronidazole from single solvents and binary solvent systems in porcine skin.

Methods: Benzyl alcohol (BA), Transcutol^® P (TC), and propylene glycol (PG) were selected as single solvents for in vitro permeation experiments. Binary solvent systems were prepared from combinations of these solvents (50:50). Permeation experiments were conducted at 32 ± 1°C with metronidazole 1% (w/v) solutions. The receptor compartment comprised of PBS (pH 7.3 ± 0.2) and 10 μL of the test solution representing a finite dose of 10 μL/cm², was applied evenly on the donor compartment. Samples were collected at different time points over 24 h and all collected samples were analyzed by HPLC. Mass balance evaluation was also conducted to confirm the total recovery of metronidazole relative to the applied dose.

Results: For the single solvents, the 24 h cumulative permeation amounts of metronidazole from BA, TC, and PG were 2.76 ± 1.17, 4.65 ± 1.10, and 2.76 ± 0.45 μg/cm², respectively (mean ± SD, n ≥ 3), with significantly higher permeation of metronidazole from TC compared with BA and PG (p < 0.05). For PG, the amount of metronidazole retained in the skin (16.17 μg ± 4.40 μg) was higher than the amount that permeated into the receptor medium (2.77 μg ± 0.73 μg, p < 0.05). The total permeation proportion of metronidazole from the PG system, calculated as the percentage of the amount extracted from the skin and recovered in the receptor fluid, was 21.25% ± 5.67%. For the binary solvent systems, the 24 h cumulative permeation of metronidazole from TC-PG (75.08 ± 14.55 μg/cm²) and BA-PG (55.90 ± 15.75 μg/cm²) was significantly higher than for TC-BA (4.98 ± 3.15 μg/cm²) (mean ± SD, n = 5, p < 0.01). Among the binary system permeation studies, TC-BA resulted in the lowest cumulative permeation amount. Compared with neat PG, the addition of either BA or TC to PG significantly increased the skin permeation of metronidazole (p < 0.01). For the three binary solvent systems, there were no significant differences in the amount of metronidazole retained within the skin (p > 0.05).

Conclusion: PG is a common component in marketed topical formulations of metronidazole¹. Previous studies have reported a percentage skin permeation > 30% for metronidazole in PG, higher than the values observed for the present study². This difference might be attributed to the different skin models employed as well as differences in the applied dose (80.6 μg/cm² vs. 100 μg/cm²). Reported cumulative permeation values for marketed 0.75% (w/w) metronidazole formulations typically range from 3.48 to 18.41 μg/cm² over 24-48 h^2–4. The present study found that TC-PG and BA-PG systems resulted in higher metronidazole permeation than neat solvents and previously reported commercial formulations. These findings support the use of TC-PG and BA-PG binary systems as potential vehicles for this drug. The findings here also confirm that not all binary vehicles resulted in improved permeation. Compared with PG-based binary vehicles, the TC-BA vehicle showed no increase compared with the neat solvents. These results indicate that combining solvents does not necessarily lead to improved permeation, and that each binary system requires individual evaluation. To our knowledge, this is the first study to explore all binary combinations of benzyl alcohol, Transcutol^® P, and propylene glycol as vehicles for topical metronidazole delivery using the in vitro porcine ear skin model.

References: 1. Elewski, B. E. Percutaneous absorption kinetics of topical metronidazole formulations in vitro in the human cadaver skin model. Adv. Ther. 24, 239–246 (2007).
2. Alonso, C. et al. Prediction of the skin permeability of topical drugs using in silico and in vitro models. Eur. J. Pharm. Sci. 136, 104945 (2019).
3. Murthy, S. N. Characterizing the Critical Quality Attributes and In Vitro Bioavailability of Acyclovir and Metronidazole Topical Products. in Food and Drug Adiministration (FDA, U. S., 2017).
4. Arora, S. et al. Mechanistic Modeling of In Vitro Skin Permeation and Extrapolation to In Vivo for Topically Applied Metronidazole Drug Products Using a Physiologically Based Pharmacokinetic Model. Mol. Pharm. 19, 3139–3152 (2022).

Figure 1. Mass balance studies of metronidazole after 24 h finite dose permeation studies in TC, PG and BA (n≥3, mean ± SD) (*p < 0.05).

Figure 2. Mass balance studies of metronidazole after 24 h finite dose permeation studies