(W1130-09-48) Comparing the Performance of Metronidazole Topical Gels with Variant Concentrations of Polyethylene Glycol (PEG) 400 in the Formulation

Purpose: Evaporative metamorphosis of topical products can result in significant quantitative changes in the formulation composition and a dynamic change in the degree of saturation of the active pharmaceutical ingredient (API) as solvents in the formulation evaporate. Topical products having differences in the degree of saturation-time profiles of the API may have differences in bioavailability. Previously, we demonstrated that it may be feasible to utilize fractional solubility as a measure of degree of saturation, in conjunction with in vitro permeation testing (IVPT), to evaluate the influence of quantitative differences in inactive ingredients (i.e., polyethylene glycol (PEG)-200) on the performance of topical gels containing various APIs (i.e., metronidazole, diclofenac sodium, lidocaine). The current series of three abstracts report studies that are aimed to assess the generalizability of the phenomenon by studying additional API and solvent combinations. This first abstract focuses on evaluating the influence of quantitative differences in PEG-400 on the performance of metronidazole topical gels.

Methods: Five metronidazole topical gels, 0.5% w/w, were prepared using PEG-400, hydroxyl ethyl cellulose, xanthan gum, sodium benzoate, ethylene-diamine-tetra acetic acid (EDTA), and water. The gels contained 22.5%, 27%, 30%, 33%, and 37.5% w/w PEG-400. The 30% w/w PEG-400-containing gel was considered as the reference gel. The PEG concentrations in the rest of the gels represent ± 10% and ± 25% quantitative differences compared to 30% w/w in the reference gel. An assessment of critical quality attributes (CQAs) of the gels including water activity, density, pH, and rheological characteristics (n=3) were carried out. An in situ drying study was performed on human cadaver skin in Franz diffusion cells for all the formulations. The gels were sampled from the donor compartment periodically for up to 6h. The samples were subjected to content assays for water, PEG-400, and metronidazole (n=3). The saturation solubility of metronidazole in PEG-400: water binary solutions was determined (n=3). Fractional solubility is calculated as the ratio of the concentration of API in the formulation to the saturation solubility of the API in the same formulation at any given time. A semi-infinite dose IVPT study was performed on human cadaver skin (3 skin donors and 6 skin sections per skin donor), using Franz diffusion cells and a dose of 300 mg/cm². The receptor solution was sampled every hour for the first 6h, and thereafter, every 4h up to 24h. The correlation between the fractional solubility profile and the IVPT profile was investigated. Data were presented as mean ± SD, except for IVPT data from three skin donors, which are presented as mean ± SEM.

Results: Results of characterization of CQAs are shown in Table 1. A non-Newtonian shear thinning flow behavior was observed with all the gels. The saturation solubility of metronidazole in the PEG-400: water binary solutions increased from 11.82 ± 1.08 to 18.32 ± 0.73 mg/mL as the PEG-400 concentration increased from 0% to 40% followed by a small decline at 50% PEG-400 concentration (17.92 ± 0.72 mg/mL). The in situ drying studies revealed that modest differences were observed in the magnitude of the fractional solubility profile of metronidazole between the ± 10% PEG-400 containing gels and the reference gel. The ± 25% PEG-400 containing gels had greater differences and more rapid increases in fractional solubility profiles of metronidazole than the reference gel. In alignment with this observation, the IVPT flux profiles of the ± 10% PEG-400 containing gels were similar to that of the reference gel, while the IVPT flux profiles of the ± 25% PEG-400 containing gel were different from that of the reference gel. A linear correlation was observed between the AUC_0-6hr (of the fractional solubility vs. time profile) and the AUC_0-6hr (obtained from the IVPT flux profile).

Conclusion: The current study suggests that ± 10% change in PEG 400 concentration compared to 30% w/w PEG-400 concentration in the reference metronidazole gel may not significantly impact the bioavailability of the API from these formulations. However, ± 25% alterations in the concentration of PEG-400 may impact the rate of permeation of metronidazole gels due to changes in the degree of saturation and thereby the thermodynamic activity. The data further supports that product performance of topical products may be primarily driven by thermodynamic activity of the API in the formulation.

Acknowledgements: This project is supported by the Food and Drug Administration (FDA) of the U.S.Department of Health and Human Services (HHS) as part of a grant (U01FD006507) with 100 percent funded by FDA/HHS. The views are those of the author(s)and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the U.S.Government.

Table 1: Critical quality attributes (CQAs) of 5 metronidazole gels that varied in the concentration of polyethylene glycol-400 (PEG-400). The reference gel had 30% w/w of PEG-400 and was named as M.PEG-F30.Ref. The gels with ±10% and ±25% differences in the concentration of PEG relative to the reference gel were named as M.PEG-F10± and M.PEG-F25±.