James J. Ferry

Properties of adhesive tapes used for stratum corneum stripping

Abstract The effectiveness of three adhesive tapes, 3Ms No. 810, No. 845 and No. 850, in stripping stratum corneum from hairless mouse skin, was compared by measuring transdermal water loss (TEWL) and distribution profiles of a marker, minoxidil, from a solution formulation. While No. 850 tape failed to increase TEWL perceptively even after 24 strippings, both No. 810 and 845 tapes effectively removed the whole stratum corneum, at least as reflected in TEWL measurements. TEWL specifically increased incrementally from somewhere between 4 and 8 g/m 2 per h to 120 g/m 2 per h. From both TEWL measurements and distribution profiles of minoxidil in skin 2 h post-application of its formulation, it appears that the 3M No. 845 tape more efficiently removes stratum corneum than 3M No. 810 tape. The difference between No. 810 and No. 845 tapes in stripping formulation-treated skin held in a diffusion cell was application-time dependent, since the No. 845 tape harvested no more minoxidil than the No. 810 tape at 12 and 24 h following application of the formulation.

Influence of Application Time and Formulation Reapplication on the Delivery of Minoxidil through Hairless Mouse Skin as Measured in Franz Diffusion Cells

Relationships are drawn between the extent of topical delivery of test compounds in solution and the period of residence of their formulation on the skin. The studies were performed using in vitro diffusion cell techniques and a test formulation containing 2% 3H-minoxidil dissolved in 60% ethanol, 20% water and 20% 14C-propylene glycol. The permeation of propylene glycol was effectively halted upon cleansing the skin surface; the skin had very little reservoir capacity for this substance. However, the rate of delivery of minoxidil was only slowed but not stopped upon cleansing. The suggestion here is that a reservoir of minoxidil is formed in the skin which is capable of sustaining an appreciable input of drug even after the skins surface is scrupulously cleaned. Assay of epidermal concentrations of these species not only confirms the existence of the minoxidil reservoir but also shows that the degree of its tissue concentration is proportional to the time of residence of the formulation on the skin surface. Reapplication of blank vehicle to the cleansed surface had little to no effect on the permeation of the minoxidil and was similarly without effect on that of propylene glycol. While it comes as no surprise that formulation residence time is an important variable in topical delivery, this study demonstrates the complexities of quantitative dependencies of delivery on residence time.

Solvent effects on the harvesting of stratum corneum from hairless mouse skin through adhesive tape stripping in vitro

Abstract 125 μl of a propylene glycol/ethanol/water vehicle were applied for various lengths of time to 1.77 cm 2 area of excised hairless mouse skin sections held in in vitro diffusion cells. After removal from the cell, each skin section was stripped repeatedly with a non-hygroscopic polypropylene tape. The amount of tissue removed in each strip was determined after allowing the volatile solvents to evaporate. Weights were corrected for residual propylene glycol and water, the amounts of which were determined radioisotopically. More tissue was harvested in the first and second strips from skin conditioned with the vehicle for more than 12 h. The effect of vehicle treatment on stripping properties precludes one from determining drug and vehicle concentration gradients in the stratum corneum at different treatment times by direct comparison of corresponding strips. While it does not appear that a penetrants deposition as a function of time can be followed easily and directly by stripping and then quantifying the drug (or solvent) in the respective layers, the stripping technique may still be useful in separating stratum corneum (or epidermis) from dermis.

Influence of tretinoin on the percutaneous absorption of minoxidil from an aqueous topical solution

Nineteen healthy male volunteers completed a three‐way, randomized, crossover study to determine the effect of the synthetic retinoid, tretinoin, on percutaneous absorption of minoxidil. Subjects received, for 20 days, twice‐daily administrations of 1 ml of an aqueous 2% topical minoxidil solution either alone, with once‐daily applications of a 0.05% tretinoin cream, or with once‐daily applications of a vehicle control cream. When minoxidil was coadministered with tretinoin cream, minoxidil absorption was increased nearly threefold, compared with a 1.3‐fold increase in absorption observed with coadministration of vehicle control cream. Transepidermal water loss measurements, which are sensitive to changes in stratum corneum function, were also significantly increased with tretinoin. No treatment‐related changes in stratum corneum thickness were observed on the basis of skin biopsy analysis. The findings indicate that percutaneous minoxidil absorption is enhanced by tretinoin as a result of increased stratum corneum permeability.

Drug and Vehicle Deposition from Topical Applications: Localization of Minoxidil within Skin Strata of the Hairless Mouse

The cutaneous bioavailability of topical 2% minoxidil solution was verified in live hairless mice. Minoxidil and propylene glycol deposition on the skin surface, epidermis and dermis from the single-dose in vivo study were compared with the results from previous in vitro studies. A distinct difference is apparent in the epidermis where the in vitro values are 11-22 times higher than the in vivo values for minoxidil and 8-16 times higher for propylene glycol. The differences were not as great in the dermis. Percutaneous absorption of the drug appeared to be a very small fraction of the applied dose. Similarly shaped stratum corneum and plasma concentration profiles and the relatively constant dermal profiles of minoxidil and propylene glycol open the possibility of transappendageal routes being involved in percutaneous absorption. The greater amount of drug and vehicle found in the dermis from in vitro studies can be explained by the absence of dermal clearance. The overestimation in the amount of drug found in the epidermis in vitro may also be attributable to poor dermal clearance. On the whole, the study raises questions about the use of in vitro tissue dispositions for bioavailability assessment and bioequivalence demonstration.

Pharmacokinetics of Cefpodoxime Proxetil in Healthy Young and Elderly Volunteers

The influence of age on the pharmacokinetics of cefpodoxime was evaluated in 12 elderly (ages 65–85 years) and 12 weight‐ and sex‐matched young (ages 20–33 years) subjects, each of whom received two cefpodoxime proxetil 200‐mg tablets every 12 hours for 14.5 days. Serial blood samples and urine were collected after the first dose on day 1, after the morning dose on day 8, and after the last (morning) dose on day 15. Plasma and urine samples were assayed for cefpodoxime concentrations using HPLC methods. Within each age group, mean pharmacokinetic parameters determined on day 1 were similar to corresponding values on days 8 and 15, indicating that cefpodoxime does not accumulate after twice‐daily dosing of cefpodoxime proxetil. Based on this result, parameters were pooled across days in each age group. No significant differences were observed between healthy and elderly volunteers in area under the plasma concentration‐time curve for the 12‐hour dosing interval, peak plasma concentration, or time to peak concentration. Mean urinary excretion and renal clearance of cefpodoxime were significantly lower in elderly subjects. Differences in renal clearance were attributed to the corresponding age‐related reduction that was noted in creatinine clearance values, whereas the lower urinary excretion of cefpodoxime probably reflected slightly reduced systemic drug absorption in the elderly. Differences in these parameters between groups were less than 30%, and were unlikely to be of clinical importance. The data indicate that dose adjustment of cefpodoxime in elderly subjects having normal (age‐adjusted) creatinine clearance values is not required.

Hemodynamic effects of minoxidil following intravenous infusions in untreated hypertensive patients

Clinical Pharmacology & Therapeutics (1996) 59, 166–166; doi: 10.1038/sj.clpt.1996.162