(M1430-11-73) Impact of Quantitative Differences in an Inactive Ingredient on the Performance of Topical Products Containing Lidocaine or Diclofenac Sodium

Purpose: Evaporative metamorphosis of topical products can lead to significant changes in the quantitative composition of the formulation. As the solvent(s) evaporate, the concentration of solubilized drug increases in the diminishing amount of solvent(s), typically up to the saturation solubility of the active pharmaceutical ingredient (API). The dynamic change in the degree of saturation of the API may impact the bioavailability of the API from a topical product. 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. Previously, we demonstrated that it may be feasible to utilize fractional solubility profiles, in conjunction with in vitro permeation testing (IVPT), to evaluate the impact of quantitative differences in inactive ingredients on the performance of topical products using metronidazole topical gels as a model system. The purpose of the current study is to assess the generalizability of the phenomenon by studying additional APIs, i.e., lidocaine and diclofenac sodium, which, compared to metronidazole, are expected to have more substantial differences in fractional solubility profiles in response to changes in inactive ingredient concentration.

Methods: For lidocaine and diclofenac sodium, topical gels (0.25% w/w and 0.5 %w/w, respectively) comprised of polyethylene glycol (PEG-200), ethylene-diamine-tetraacetic acid (EDTA), sodium benzoate, hydroxyethylcellulose and water were manufactured. The concentration of PEG-200 was varied across the formulations from 1% to 20% w/w. The saturation solubility of lidocaine and diclofenac sodium in PEG-200: water binary solutions was determined (n=3). An 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 the API (n=3). Finally, a semi-finite dose IVPT study was 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. Correlation of the fractional solubility profile and the IVPT profile was investigated.

Results: The saturation solubility (n=3, mean ± SD) of each API greatly increased as the PEG-200 concentration increased from 0% to 100% in the PEG-200: water binary solutions (4.12 ± 0.51 to 215.71 ± 14.29 mg/mL for lidocaine, and 17.07 ± 0.26 to 246.77 ± 50.81 mg/mL for diclofenac sodium). The in-situ drying rate studies revealed that there was a greater change over time in fractional solubility profile for each API in the 1% PEG-200 gel compared to the 10% PEG gel and 20 % PEG gel. More specifically, a relatively rapid increase was observed in the fractional solubility profile for each API in the 1% PEG-200 gel compared to the other two gels. In alignment with this observation, the IVPT flux profiles for each API in the 1% PEG-200 gel were higher compared to those for the 10% PEG gel and 20% PEG gel. A relatively linear correlation was observed between the AUC_0-6hr (of the fractional solubility vs. time profile) and the AUC_0-6hr (obtained from IVPT flux profile). The data suggests that the time course of degree of saturation may be the primary determinant of formulation performance in case of lidocaine and diclofenac sodium gels, similar to results previously obtained for metronidazole gels.

Conclusion: The current study further supports that it may be feasible to utilize fractional solubility profiles in conjunction with IVPT to evaluate the impact of quantitative differences in inactive ingredients on the performance of topical products with quantitative differences in formulation compositions, which may occur during evaporative metamorphosis. Additional research is underway to develop and generalize such methodologies for multiple inactive ingredients.

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.