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Characterization of Temperature Profiles in Skin and Transdermal Delivery System When Exposed to Temperature Gradients In Vivo and In Vitro

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Abstract

Purpose

Performance of a transdermal delivery system (TDS) can be affected by exposure to elevated temperature, which can lead to unintended safety issues. This study investigated TDS and skin temperatures and their relationship in vivo, characterized the effective thermal resistance of skin, and identified the in vitro diffusion cell conditions that would correlate with in vivo observations.

Methods

Experiments were performed in humans and in Franz diffusion cells with human cadaver skin to record skin and TDS temperatures at room temperature and with exposure to a heat flux. Skin temperatures were regulated with two methods: a heating lamp in vivo and in vitro, or thermostatic control of the receiver chamber in vitro.

Results

In vivo basal skin temperatures beneath TDS at different anatomical sites were not statistically different. The maximum tolerable skin surface temperature was approximately 42–43°C in vivo. The temperature difference between skin surface and TDS surface increased with increasing temperature, or with increasing TDS thermal resistance in vivo and in vitro.

Conclusions

Based on the effective thermal resistance of skin in vivo and in vitro, the heating lamp method is an adequate in vitro method. However, the in vitro-in vivo correlation of temperature could be affected by the thermal boundary layer in the receiver chamber.

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Abbreviations

FDA:

U.S. Food and Drug Administration

HPLC:

High performance liquid chromatography

IVIVC:

In vitro-in vivo correlation

IVPT:

In vitro permeation test

PBS:

Phosphate buffered saline

PID:

Proportional integral derivative

q skin :

Heat flux across the skin

q TDS :

Heat flux across the TDS

R ABL :

Aqueous boundary layer thermal resistance

R s :

Skin thermal resistance in vivo

R sts :

Split-thickness skin thermal resistances in vitro

R TDS :

TDS thermal resistance

RLD:

Reference listed drug

T derm :

Temperature of the tissue around blood circulation under the skin

T receiver :

Receiver solution temperature in diffusion cell

T skin/receiver :

Temperature at the skin/receiver interface

T TDS :

TDS surface temperature

T TDS/skin :

Skin surface temperature under TDS

TDS:

Transdermal delivery systems

TDS-1:

1-layer model TDS

TDS-5:

5-layer model TDS

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors thank Drs. Arjang Talattof and Elena Rantou for helpful discussion and Craig Dixon at ThermTest Inc. for performing the thermal resistance analysis of the nicotine TDS. Funding for this work was made possible, in part, by the FDA through grant U01FD004942. 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. The views expressed in this manuscript do not reflect the official policies of the FDA or the U.S. Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Authors and Affiliations

  1. Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, 231 Albert Sabin Way, MSB # 3005, Cincinnati, Ohio, 45267-0514, USA

    Qian Zhang, Michael Murawsky, Terri LaCount, 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. Division of Therapeutic Performance, Office of Research and Standards, Office of Generic Drugs, U.S. Food and Drug Administration, Silver Spring, Maryland, 20993, USA

    Bryan Newman, Priyanka Ghosh & Sam G. Raney

Authors
  1. Qian Zhang
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  2. Michael Murawsky
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  3. Terri LaCount
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  4. Jinsong Hao
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  5. Gerald B. Kasting
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  6. Bryan Newman
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  7. Priyanka Ghosh
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  8. Sam G. Raney
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  9. S. Kevin Li
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Correspondence to S. Kevin Li.

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Zhang, Q., Murawsky, M., LaCount, T. et al. Characterization of Temperature Profiles in Skin and Transdermal Delivery System When Exposed to Temperature Gradients In Vivo and In Vitro . Pharm Res 34, 1491–1504 (2017). https://doi.org/10.1007/s11095-017-2171-x

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  • DOI: https://doi.org/10.1007/s11095-017-2171-x

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