(M1030-04-19) Influence of Varying Amount of an Inactive Ingredient on the Microstructure and Performance of Metronidazole Topical Gels

Purpose: Evaporative metamorphosis of topical products could lead to significant change in the degree of saturation of the active pharmaceutical ingredient (API) in the formulation over time. The dynamic change in the degree of saturation of the API may impact the bioavailability of the API from a topical product. The objective of this study was to investigate the influence of quantitative changes in an inactive ingredient on the microstructure and the performance of topical gels containing metronidazole as the API.

Methods: 5 metronidazole (0.5%w/w) topical gels comprising of polyethylene glycol (PEG-200), ethylenediaminetetraacetic acid (EDTA), sodium benzoate, hydroxyethylcellulose and water were manufactured. The concentration of PEG-200 was varied across the formulations from 5% to 25%. The drying profile of the gels were evaluated using a gravimetric method, water activity was measured using Aqualab-3, and pH was determined using a Toledo pH meter with a microprobe (n=3). An additional in situ drying study was performed on human cadaver skin in Franz diffusion cells for selected formulations. The gels were sampled from the donor compartment periodically for up to 6h. The samples were subjected to content assays for water, PEG-200, and metronidazole (n=3). The saturation solubility of metronidazole in PEG-200: water compositions was also determined. Fractional solubility (α) is used in the current study as a measure of the degree of saturation; the parameter is defined 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. Finally, a semi-finite dose in vitro permeation testing (IVPT) study was also performed across human cadaver skin using Franz diffusion cells (n=3 skin donors, 6 skin sections per skin donor) using a dose of 300 mg/cm². The receptor solution was sampled every hour for the first 6h, and thereafter, every 4h up to 24h. An infinite dose IVPT study was also performed as a control to demonstrate the sensitivity of the IVPT method. The IVPT data are presented as mean >± SEM. Correlation of the fractional solubility profile and the in vitro permeation profile was investigated.

Results: The pH of all the gels were about 7.0. Although the in situ drying profiles demonstrated slight differences across gels, the fractional solubility vs. time profiles were relatively stable and comparable across the three selected gels. There were no significant differences in the observed permeation profiles for the three gels in the semi-infinite dose IVPT study, and the data were in alignment with the fractional solubility profiles. The infinite dose study suggested that the IVPT method used in the study is sensitive and suitable for detection of differences in permeation, when such differences exist.

Conclusion: The current study suggests that it may be feasible to utilize the fractional solubility profiles in conjunction with IVPT to evaluate the impact of quantitative differences in inactive ingredients on performance of topical products during evaporative metamorphosis. However, additional research with multiple active and inactive ingredients is necessary to develop and generalize such methodologies.

Acknowledgments: 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) totaling $500,000 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.