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

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.

Modeling Temperature-Dependent Dermal Absorption and Clearance for Transdermal and Topical Drug Applications.

A computational model was developed to better understand the impact of elevated skin temperatures on transdermal drug delivery and dermal clearance. A simultaneous heat and mass transport model with emphasis on transdermal delivery system (TDS) applications was developed to address transient and steady-state temperature effects on dermal absorption. The model was tested using representative data from nicotine TDS applied to human skin either in vitro or in vivo. The approximately 2-fold increase of nicotine absorption with a 10°C increase in skin surface temperature was consistent with a 50-65 kJ/mol activation energy for diffusion in the stratum corneum, with this layer serving as the primary barrier for nicotine absorption. Incorporation of a dermal clearance component into the model revealed efficient removal of nicotine via the dermal capillaries at both normal and elevated temperatures. Two-compartment pharmacokinetic simulations yielded systemic drug concentrations consistent with the human pharmacokinetic data. Both in vitro skin permeation and in vivo pharmacokinetics of nicotine delivered from a marketed TDS under normal and elevated temperatures can be satisfactorily described by a simultaneous heat and mass transfer computational model incorporating realistic skin barrier properties and dermal clearance components.

A Composite Model for the Transport of Hydrophilic and Lipophilic Compounds Across the Skin: Steady-State Behavior.

A porous pathway feature has been added to an existing skin diffusion model to extend the range of applicability to highly polar solutes that do not readily diffuse across the stratum corneum (SC) lipid/corneocyte matrix. The porous pathway consists of 2 components: Pathway A is appendageal and is implemented as an array of aqueous shunts (the macropores), which themselves have microporous walls with transient aqueous pores (the micropores). Two varieties of shunts are discussed, one representing a terminal hair follicle and the other representing an eccrine sweat duct; however, the focus here is on the hair follicle. Pathway B is transcellular, with lipid-phase transport accomplished through defects or breaks in the bilayer lipid structure. The composite model admits polar solutes into the skin in a size-selective manner with an effective micropore radius of 1.6 nm. Steady-state permeabilities, desorption rates from isolated SC, and SC/water partition coefficients of both polar and lipophilic solutes are effectively explained.

Size and Charge Dependence of Ion Transport in Human Nail Plate.

The electrical properties of human nail plate are poorly characterized yet are a key determinate of the potential to treat nail diseases, such as onychomycosis, using iontophoresis. To address this deficiency, molar conductivities of 17 electrolytes comprising 12 ionic species were determined in hydrated human nail plate in vitro. Cation transport numbers across the nail for 11 of these electrolytes were determined by the electromotive force method. Effective ionic mobilities and diffusivities at infinite dilution for all ionic species were determined by regression analysis. The ratios of diffusivities in nail to those in solution were found to correlate inversely with the hydrodynamic radii of the ions according to a power law relationship having an exponent of -1.75 ± 0.27, a substantially steeper size dependence than observed for similar experiments in skin. Effective diffusivities of cations in nail were 3-fold higher than those of comparably sized anions. These results reflect the strong size and charge selectivity of the nail plate for ionic conduction and diffusion. The analysis implies that efficient transungual iontophoretic delivery of ionized drugs having radii upward of 5 Å (molecular weight, ca. ≥ 340 Da) will require chemical or mechanical alteration of the nail plate.