(W1230-09-48) Understanding the Influence of Occlusion on Oxybutynin Permeation from a Transdermal Gel Deposited Film Using IVPT

Purpose: Many factors, such as skin hydration, heat, and damage to the epidermis, can affect how a drug is absorbed through the stratum corneum (SC). Occlusion, or covering, of the skin following topical application of a drug product can greatly affect the formulation metamorphosis and hydration of the SC, which influences the drug absorption rate. The objective of this project is to investigate how occlusion can affect drug permeation of oxybutynin from a transdermal gel deposited solid film using the in vitro permeation test (IVPT) model. Oxybutynin is an anticholinergic drug used to help treat overactive bladder and is highly lipophilic. Oxybutynin chloride 10% topical gel was tested to determine how the occlusion window (7-10 h post gel application) would impact oxybutynin absorption through the skin by measuring flux and cumulative amount absorbed. This enabled development of an in vitro-in vivo correlation (IVIVC).

Methods: A 25 h IVPT study was conducted using abdominal human skin. Each IVPT consisted of four baseline diffusion cells without occlusion, and four cells with 3 h of occlusion. In total, four IVPT studies were completed with different human skin donors. Excised human skin was placed in In-Line flow-through diffusion cells maintained at a skin surface temperature of 32°C, and 0.9% saline solution with 0.005% gentamicin sulfate was used as the receiver solution. All cells were dosed with 9.5 mg of gel and eight time points were collected. The occlusive film was applied at 7 h, and then removed at 10 h. The gel was removed from the skin at 12 h and the IVPT was completed at 25 h. Oxybutynin concentration was measured by HPLC to determine flux and cumulative amount absorbed. The IVPT occlusion period and formulation removal time were based on previous human pharmacokinetic (PK) study data, so an IVIVC could be established using Pumas software. Intravenous (IV) PK data was fitted using a three-compartment model and an IVIVC model was developed comparing in vitro and in vivo flux. Light microscopy was used to visualize gel formulation metamorphosis on the surface of the skin vs. an inert impermeable surface.

Results: The mean flux at each time point was determined and the flux values for the occluded cells were significantly greater (p < 0.05) compared to the baseline. The mean flux for the occluded cells at 12 h was 1.027 µg/cm²h (± 0.283) and non-occluded baseline had a mean flux of 0.086 µg/cm²h (± 0.050). The maximum mean flux at 16 h for the occluded cells was 1.266 µg/cm²h (± 0.606) and the maximum mean flux for the non-occluded baseline measurement was 0.434 µg/cm²h (± 0.253). A similar trend with serum concentration increase was also observed in a previous human study with oxybutynin occlusion. A Level A IVIVC was achieved with the IVPT flux and clinical study serum PK data.

Conclusion: Occlusion was used over the area of gel formulation application and had a significant impact on the oxybutynin absorption, even after the drug formulation was removed from the skin surface. Additional research is needed to elucidate the mechanisms that led to enhanced delivery following occlusion 7 h after the application of the drug product. A more comprehensive study should be conducted to determine the potential real-world effects of occlusion on drug permeation, since it is evident that significant drug absorption can occur from residual formulation excipients that undergo metamorphosis under occlusion. The IVIVC will enable evaluation of various gel exposure scenarios under occlusion using IVPT, and help to predict the desired and undesired drug absorption from similar transdermal gel formulations.

Acknowledgements: The previous clinical study was funded by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award [FAIN] (Research Award U01FD004955). This work was supported in part by the University of Maryland Baltimore, School of Pharmacy Mass Spectrometry Center (SOP1841-IQB2014). Biospecimens were provided by the NCI funded Cooperative Human Tissue Network (CHTN).

Figure 1. Flux profile (A) and cumulative amount (B) of oxybutynin from occluded and unoccluded diffusion cells (n=4 donors; 4 replicates/donor; Mean ± SD).

Figure 2. Oxybutynin serum concentration profiles from a previous clinical trial (n=12 volunteers; Mean + SE).