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Evaluation of Heat Effects on Transdermal Nicotine Delivery In Vitro and In Silico Using Heat-Enhanced Transport Model Analysis

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Abstract

A combined experimental and computational model approach was developed to assess heat effects on drug delivery from transdermal delivery systems (TDSs) in vitro and nicotine was the model drug. A Franz diffusion cell system was modified to allow close control of skin temperature when heat was applied from an infrared lamp in vitro. The effects of different heat application regimens on nicotine fluxes from two commercial TDSs across human cadaver skin were determined. Results were interpreted in terms of transport parameters estimated using a computational heat and mass transport model. Steady-state skin surface temperature was obtained rapidly after heat application. Increasing skin surface temperature from 32 to 42°C resulted in an approximately 2-fold increase in average nicotine flux for both TDSs, with maximum flux observed during early heat application. ANOVA statistical analyses of the in vitro permeation data identified TDS differences, further evidenced by the need for a two-layer model to describe one of the TDSs. Activation energies associated with these data suggest similar temperature effects on nicotine transport across the skin despite TDS design differences. Model simulations based on data obtained from continuous heat application were able to predict system response to intermittent heat application, as shown by the agreement between the simulation results and experimental data of nicotine fluxes under four different heat application regimens. The combination of in vitro permeation testing and a computational model provided a parameter-based heat and mass transport approach to evaluate heat effects on nicotine TDS delivery.

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Abbreviations

AUC:

Area under the curve

CHADD:

Controlled heat-assisted drug delivery

C :

Concentration

c adh :

Fast-release compartmental concentration in the two-layer TDS

C 0 :

TDS concentration

C max :

Maximum concentration

DE:

Dermis

D adh :

Fast-release compartmental diffusivity in the two-layer TDS

D p :

Homogeneous TDS diffusivity

D p2 :

Slow-release compartmental diffusivity in the two-layer TDS

D SC_32 :

Stratum corneum diffusivity (DSC) for 32°C

D SC_42 :

DSC for 42°C

E A :

Activation energy

IVPT:

In vitro permeation test

J max :

Maximum (peak) flux

J max_sim :

Simulation Jmax

J max_exp :

Experimental Jmax

K SCp :

SC/TDS partition coefficient

K oct :

Octanol-water partition coefficient

M f :

Total (cumulative) amount of drug permeated

M(t):

Cumulative amount of drug permeated at a given time

PBS:

Phosphate-buffered saline

PID:

Proportional-integral-derivative

SC:

Stratum corneum

T:

Temperature

t max :

Time when maximum flux occurs

t max_sim :

Simulation tmax

TDS:

Transdermal delivery system(s)

UC/UB:

University of Cincinnati/University of Buffalo

VE:

Viable epidermis

z :

Position in the membrane along the axis perpendicular to the skin surface

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Acknowledgments

The authors gratefully acknowledge the contributions to the IVPT study design by Dr. Audra Stinchcomb, Dr. Hazem Hassan, Soo Hyeon Shin, and others at the University of Maryland, as well as Dr. Bryan Newman, Dr. Robert Lionberger, and others at the FDA. The authors also thank Daniel M. Frey for his help in the laboratory.

Funding

Funding for this project was made possible, in part, by the US Food and Drug Administration (FDA) through a cooperative agreement (Research Award U01 FD004942). In response to funding opportunity announcement RFA-FD-13-015, separate research projects were awarded in parallel to the University of Cincinnati and the University of Maryland, and each institution was requested by the FDA to perform independent research with the same drug products under comparable study conditions in a manner coordinated by the FDA.

Author information

Authors and Affiliations

  1. Division of Pharmaceutical Sciences, James L Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, 45267, USA

    Terri D. La Count, Qian Zhang, Michael Murawsky, Gerald B. Kasting & S. Kevin Li

  2. Department of Pharmaceutical Science and Research, School of Pharmacy, Marshall University, Huntington, West Virginia, 25755, USA

    Jinsong Hao

  3. Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, Campbell University, Buies Creek, North Carolina, 27506, USA

    Jinsong Hao

  4. Office of Research and Standards, Office of Generic Drugs, U.S. Food and Drug Administration, Silver Spring, Maryland, 20993, USA

    Priyanka Ghosh, Kaushalkumar Dave, Sam G. Raney & Arjang Talattof

Authors
  1. Terri D. La Count
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Correspondence to S. Kevin Li.

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This article reflects the views of the authors and should not be construed to represent the US Food and Drug Administration’s views or policies. The views expressed in this paper do not reflect the official policies of the Department of Health and Human Services, nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government.

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Electronic Supplementary Material

Supplementary Figure S1

Experimental (symbols) and simulated (curve) cumulative amount data of nicotine permeation across human skin from TDS-N2 at 32°C for a single diffusion cell. (GIF 242 kb)

Supplementary Figure S2.

Representative temperature versus time plot. Insert depicts expanded time scale showing initial application of heat and PID controller adjusting heat to set value. (GIF 261 kb)

Supplementary Figure S3

Optimized (fitted) TDS-N1 flux from three models (homogeneous TDS, two-layer TDS, and adjusted two-layer TDS) in comparison to experimental flux data (symbols) at baseline and elevated temperatures, which shows the adjusted two-layer TDS model best characterizes TDS-N1 drug delivery. Heat application was for 24 h for the 42°C case (arrows). (GIF 564 kb)

Supplementary Figure S4

In vitro release test (IVRT) of nicotine release from TDS-N1 (circle symbols) and TDS-N2 (square symbols) at 32°C (open symbols) and 42°C (closed symbols) in Franz diffusion cell using a filter membrane (without skin). Heat was applied from 0-24 h for the 42°C case (arrows). Mean ± SEM, n = 11–12. (GIF 128 kb)

Supplementary Figure S5

Representative image of the release liner (left), internal membrane (middle), and backing (right) of TDS-N1. (GIF 1546 kb)

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La Count, T.D., Zhang, Q., Murawsky, M. et al. Evaluation of Heat Effects on Transdermal Nicotine Delivery In Vitro and In Silico Using Heat-Enhanced Transport Model Analysis. AAPS J 22, 82 (2020). https://doi.org/10.1208/s12248-020-00457-w

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