In vivo methods for the assessment of topical drug bioavailability

Abstract

This paper reviews some current methods for the in vivo assessment of local cutaneous bioavailability in humans after topical drug application. After an introduction discussing the importance of local drug bioavailability assessment and the limitations of model-based predictions, the focus turns to the relevance of experimental studies. The available techniques are then reviewed in detail, with particular emphasis on the tape stripping and microdialysis methodologies. Other less developed techniques, including the skin biopsy, suction blister, follicle removal and confocal Raman spectroscopy techniques are also described.

Fig. 1

Correlation between the amount of different chemicals absorbed across skin following a 30-min application and the quantity recovered in SC tape-strips after an identical, but independent, administration procedure. Redrawn from [52].

Fig. 2

Schematic representation of a dermatopharmacokinetic (DPK) study to assess topical bioequivalence between test and reference formulations containing the same drug. a In the uptake, or absorption, phase, the SC is tape-stripped immediately after each treatment time, and the drug level in the barrier is determined. b In the clearance phase, after the maximum treatment time, the SC is subsequently stripped after progressively longer periods post-removal of the formulations. CTR = control, drug-free formulation.

Fig. 3

DPK profiles of reference and test formulations containing the same drug. The parameters to be compared are the maximum drug level in the SC (C_max), the time at which this maximum level is reached (T_max) and the area under the SC quantity versus time profile (AUC).

Fig. 4

DPK profiles (means of n = 49) of three (0.025% v/v) tretinoin gel products in human stratum corneum (SC). Solid line = reference product (Retin-A); dotted line = generic formulation; dashed line = Avita gel (redrawn from (72)). At the time points indicated with an asterisk (*), a significant difference between Avita and both the reference and gel products exist (analysis of variance, Fisher’s protected least significant difference, p < 0.05).

Fig. 5

a Progressive increase of transepidermal water loss (TEWL) as a function of the absolute depth (μm) of stratum corneum removed. b The data in a, re-plotted as a linear relationship between (TEWL)⁻¹ and the depth of SC removed. The x-axis intercept equals the SC thickness.

Fig. 6

a Increase in transepidermal water loss (TEWL) as a function of the amount of SC thickness removed (x) by serial tape-stripping (n = 20). b Increase in TEWL as a function of SC thickness removed (x) normalized by the corresponding intact membrane thickness (H) for each individual.

Fig. 7

Schematic diagram of an attenuated total reflectance (ATR) device mounted on a Fourier transform infrared (FTIR) spectrometer. The sampling area of the crystal is made to contact with the treated skin site or the tape-strip. IR radiation from the spectrometer is deflected by a first mirror to the ATR crystal, in which it undergoes total internal reflection, penetrating superficially into the skin, before exiting the crystal and being re-directed to the detector.

Fig. 8

Terbinafine (TBF) concentration versus SC depth profiles in vivo (n = 5). The individual data points and the best fits of Eq. 1 to the results are shown following application a in the control formulation (EtOH-IPM, 50:50), and b in the same formulation containing 5% oleic acid. Redrawn from 46).

Fig. 9

Schematic diagram of two currently used microdialysis probes for DPK experiments. In both cases, a semi-permeable dialysis membrane collects the absorbed free drug. a Single-lumen probe: the membrane is located in the middle of the probe, and the perfusate flow is mono-directional. b Dual-lumen probe: the membrane is on the tip of the probe, and the perfusate flow is bi-directional.

Fig. 10

Penetration of lidocaine from three different formulations into the dermis of eight volunteers measured by microdialysis (from (107)).

Fig. 11

Local availability of ketoprofen applied topically from two gel formulations: assessment ain vitro in diffusion cells (upper panel), bin vivo by tape stripping (middle panel), and c by dermal microdialysis (lower panel; A.-R. Denet and V. Préat, unpublished data).