(T1130-09-49) Development of In Vitro Skin Permeation Testing Method to Assess the Bioequivalence of Topical Roflumilast Cream Formulations

Purpose: A characterization-based approach may be used for demonstration of bioequivalence (BE) of topical drug products. This approach relies on establishment of a group of evidence which may include results of in vitro BE studies, such as in vitro permeation test (IVPT) and in vitro release test (IVRT), as well as other physicochemical and structural (Q3) characterization tests, such as characterization of visual appearance and texture, phase states and microstructure, rheological behavior, pH, and specific gravity. Zoryve (roflumilast) topical cream (0.3%) has been approved for the treatment of plaque psoriasis in patients 6 years of age and older. As a complex multiphasic topical formulation, a demonstration of BE of generic roflumilast topical creams may be achieved using the characterization-based BE approach. In this regard, the current study evaluated the dermal availability of roflumilast after application of the drug product to dermatomed human cadaver skin samples. The feasibility of recommending IVPT as a component of a characterization-based BE approach for roflumilast topical cream products was also assessed.

Methods: oflumilast solubility in various solvents at both 25°C and 32°C was assessed to identify a suitable receptor solution for an IVPT study. The receptor solutions evaluated were phosphate buffered saline (PBS) (pH 7.4) with 0.02% Oleth-20, PBS (pH 7.4) with 4% bovine serum albumin (BSA), and PBS (pH 7.4). Sodium azide was added to each receptor solution at a 0.02% w/v concentration to prevent bacterial growth. Permeation of roflumilast from ZORYVE topical cream was assessed across dermatomed human cadaver skin mounted in vertical diffusion cells. Integrity of skin samples was confirmed by assessing trans-epidermal water loss (TEWL) using a vapometer. Skin samples (n=3, per donor) from four donors were dosed with 15 mg/cm² of ZORYVE topical cream. Skin temperature was maintained at 32 °C and the receptor solution was stirred at 600 rpm. Aliquot samples (700 µL) were withdrawn from the receptor solutions (15 mL) at 0.5, 1, 6, 12, 18, 24, 30, and 48 h. The receptor solution and solubility samples were quantified using a validated HPLC-UV method.

Results: The solubility of roflumilast ranged from 1.67 to 58.94 µg/mL at 25°C and from 2.22 to 71.27 µg/mL at 32°C in PBS, PBS with BSA, or Oleth-20. Because the highest solubility of roflumilast was observed in PBS with Oleth-20 at both temperatures, this receptor solution was chosen for IVPT. The amount of roflumilast that permeated across dermatomed human cadaver skin from all four donors (A-D), using three replicates per donor, gradually increased over time, up to 48 hours (Figure 1A). A consistent lag time of 6 hours was observed in drug permeation across all diffusion cells, likely due to the analytical sensitivity issues related to low drug detection. Consistent cumulative amount of roflumilast (1.2 µg/cm² of skin) permeated from donors A-C, while donor D showed slightly lower drug levels (0.74 µg/cm² of skin), which could be attributed to the inherent variability among different donors. Overall, the mean cumulative amount permeated from all four donors was 1.09 µg/cm² of skin. Additionally, as shown in Figure 1B, flux profiles typical to finite dosing were clearly observed for roflumilast in data from all donor skin samples (A-D).

Conclusion: The results suggest that it is feasible to conduct an IVPT as a component of the characterization-based BE approach for roflumilast topical creams, following adequate development and optimization of an IVPT method.

Acknowledgements: Disclaimer: This presentation reflects the views of the authors and should not be construed to represent FDA’s views or policies.

Figure 1: Cumulative amount (A) and flux (B) profiles of roflumilast permeated across human cadaver skin samples into the receptor solution of PBS with Oleth-20. The permeation data are expressed as mean values ± SD of three replicates using skin samples from four donors "A-D”.