Nabila Sekkat

Normalization of Stratum Corneum Barrier Function and Transepidermal Water Loss In Vivo

PURPOSE : To understand and account for inter-individual variations in percutaneous drug penetration and transepidermal water loss (TEWL). METHODS: TEWL is the standard measure of stratum corneum (SC) barrier function in vivo. The use of serial tape-stripping enables SC barrier efficiency to be assessed as a function of position. Previous studies have shown that TEWL increases as the barrier is removed by progressive tape-stripping. Although complete removal of the SC results in TEWL increasing to 80-100 g/m2h, inter-individual (and inter-regional) differences in SC thickness mean that different amounts of tissue have to be removed before these TEWL levels are attained. RESULTS: We show that normalization of the amount of SC removed with respect to the total Sc thickness effectively eliminates the inter-individual differences perceived in the raw data (i.e., TEWL as a function of tape-stripping number or as a function of cumulative SC mass removed). CONCLUSIONS: The results of this study demonstrate clearly that the objective evaluation of topical drug bioavailability (or of topical bioequivalence between different formulations) using tape-stripping methodology, as has been recently advocated by the U.S. Food & Drug Administration, must involve a quantitative determination of the amount of SC removed. In this way, the significant inter-individual differences typically observed in the penetration measurements may be decreased.

Porcine ear skin as a model for the assessment of transdermal drug delivery to premature neonates.

AbstractPurpose. The purpose of this study was (i) to validate differentially tape-stripped, porcine skin as an in vitro model for the evaluation of transdermal drug delivery (TDD) to premature neonates, (ii) to determine whether the model could estimate neonatal skin permeability as a function of postconceptional age (PCA), and (iii) to demonstrate that iontophoretic delivery permits precise control of drug input independent of skin barrier function. Methods. Passive permeation of caffeine, phenobarbital, and lidocaine across tape-stripped porcine skin barriers was measured. Iontophoretic delivery of lidocaine across skins with different barrier competencies was also evaluated. Results. For all drugs, passive permeation correlated with skin barrier function; that is, with transepidermal water loss (TEWL): Jss = A ⋅ exp[B ⋅ TEWL]. Combining this result with a previously derived dependence of TEWL upon the PCA of premature neonates in vivo allowed a relative value of Jss to be predicted for a given PCA. Comparison of these predictions showed excellent agreement with experimental data reported for diamorphine. Iontophoretic lidocaine delivery was precisely controllable independent of barrier competency. Conclusions. Porcine skin, in vitro, differentially tape-stripped to specific barrier competencies, is a useful model to explore TDD in premature neonates. The potential for iontophoresis to provide improved dose control and adjustment, irrespective of skin barrier maturity, is established.

Reverse iontophoretic monitoring in premature neonates: feasibility and potential.

Premature neonates represent a fragile patient population, often subjected to intensive clinical care and multiple drug therapy, which must be monitored carefully and continuously. The difficult and painful nature of repetitive blood sampling, particularly in this population, has provided considerable impetus for the development of noninvasive methods for monitoring blood analytes. Reverse iontophoresis, a relatively new technology already used for the transdermal monitoring of blood glucose levels in adults, may be particularly well-suited to exploit the unique properties of preterm neonatal skin. The underdevelopment of the premature infants epidermis, and more specifically the stratum corneum (SC), results in an increased permeability to molecular transport. In this study, we have investigated the feasibility of reverse iontophoretic monitoring of two model drugs, caffeine and theophylline, which are often administered to premature neonates. To this purpose, tape-stripped porcine skin in vitro, which has been previously demonstrated to be an excellent model for premature neonatal skin, was employed. Reverse iontophoresis across intact membranes enabled a quantifiable extraction of both drugs predominantly at the cathode compartment. The mechanism of extraction of these essentially neutral drugs (caffeine and theophylline being uncharged at pH 7.4) was electroosmosis. However, when the SC was removed by progressive tape-stripping, the amounts of drugs extracted by reverse iontophoresis were equivalent to those obtained by passive diffusion. In these circumstances, therefore, the benefit and usefulness of the applied electric field had been lost. In summary, the absence of an at least partially functional skin barrier obviates, in the case of neutral molecules, the control (and directional transport) offered by iontophoresis; in contrast, for ionized species, where the principal iontophoretic transport mechanism is electromigration, the approach should be valid.