Evaluation of Heat Effects on Fentanyl Transdermal Delivery Systems Using In Vitro Permeation and In Vitro Release Methods

Abstract

Experimental conditions that could impact the evaluation of heat effects on transdermal delivery systems (TDS) using an in vitro permeation test (IVPT) and in vitro release testing (IVRT) were examined. Fentanyl was the model TDS. IVPT was performed using Franz diffusion cell, heating lamp, and human skin with seven heat application regimens. IVRT setup was similar to IVPT, without using skin. Dissolution study was conducted in a modified dissolution chamber. The activation energy of skin permeation for fentanyl was determined using aqueous solution of fentanyl. In IVPT, the increase of temperature from 32 °C to 42 °C resulted in a 2-fold increase in flux for fentanyl TDS, consistent with the activation energy determined. The magnitude of flux increase was affected by the heat exposure onset time and duration: higher flux was observed when heat was applied earlier or following sustained heat application. Heat induced flux increases could not be observed when inadequate sampling time points were used, suggesting the importance of optimizing sampling time points. Drug release from TDS evaluated using IVRT was fast and the skin was the rate-limiting barrier for TDS fentanyl delivery under elevated temperature.

Keywords: Fentanyl; Heat effect; In vitro drug release testing (IVRT); In vitro permeation test (IVPT); Skin permeation; Transdermal; Transdermal delivery system (TDS); Transport activation energy.

Fig. 1.

Comparison of the thermal images at 32 °C (left image) and 42 °C (right image) for TDS-Z (Sp1), TDS-V (Sp2) and TDS-M (Sp3) in a calibration study. The table shows the temperatures measured by the temperature probes and IR thermal camera. The temperature images of TDS (circular shapes) were obtained from the IR thermal camera. A circulating water-bath was used to control the temperature on a surface and the three TDS were adhered on this temperature-controlled surface with one temperature probe at the TDS/surface interface and another temperature probe at the surface of the TDS backing. The temperature measurements from the probes and IR thermal camera in the calibration study are presented in the table (average of at least two measurements). Unlike TDS-Z and TDS-M, which have a transparent appearance on the TDS backing, TDS-V has a flesh color on its backing layer. The lower temperatures on the IR thermal camera could be due to lower emissivity from the colored backing of TDS-V.

Fig. 2.

Profiles of fentanyl delivery rates for TDS-Z (diamonds), TDS-V (triangles) and TDS-M (squares) under (a) control condition at 32 °C (Protocol 1) and the conditions of heat application for (b) 11–12 h; (c) 18–19 h; (d) 6–72 h; (e) 24–72 h; (f) 48–72 h; (g) 6–7, 18–19 and 48–72 h; and (h) 0–72 h at 42 °C (Protocols 2–8). Mean ± SEM, n = 4 skin donors (3–4 skin samples as replicates of each skin donor). Arrows indicate the time when TDS was removed.

Fig. 3.

Effect of sampling interval on the fentanyl delivery rate for TDS-Z when heat was applied from 18 to 19 h (Protocol 3). Open diamonds represent the initial 72 h study results without sampling time points at 20 and 21 h. Solid diamonds represent the results of the repeated study including additional sampling time points at 20 and 21 h to capture the fluxes at 19.5 h and 20.5 h. The repeat experiment was only conducted for the duration of 24 h instead of 72 h because no appreciable flux was observed after 24 h when the TDS was removed at 19 h as shown in the initial study. Mean ± SEM, n = 4 skin donors (3 and 2–3 skin samples as replicates of each skin donor for the protocols with and without 20 and 21-h sampling time points, respectively).

Fig. 4.

Effect of heat application duration on the fentanyl delivery rate for TDS-Z. Two heat application protocols were compared: 6–7 h heat from the multiple heating protocol (open symbols, Protocol 7) and 6–72 h heat (closed symbols, Protocol 4). Mean ± SEM, n = 4 skin donors (3–4 skin samples as replicates of each skin donor).

Fig. 5.

Drug release profiles at 32 °C (blue open symbols) and 42 °C (red closed symbols) in the IVRT study using filter membrane in the Franz diffusion cell (squares) and the dissolution study in the vial (circles) for (a) TDS-Z, (b) TDS-V, and (c) TDS-M. The secondary y-axis shows the delivery rates corresponding to the fluxes of the TDS products (e.g., 140 μg/cm²/h ≈ 3200 μg/h for TDS-Z) for comparison to the data in Fig. 2. The durations of the IVRT and dissolution studies were 72 h and 24 h, respectively. Data after 24 h are not presented in the figure because drug release after 24 h was negligible compared to those in the first 24 h (see Fig. S5, Supplemental Materials). Mean ± SEM (5–6 replicates for each temperature condition in the IVRT study, and 3–4 replicates for each temperature condition in the dissolution study). Some error bars are small and overlap with the symbols.