R. Obach

In vitro based index of topical anti-inflammatory activity to compare a series of NSAIDs

The aim of the present work was to generate an index to predict topical efficiency of a series of nonsteroidal anti-inflammatory drugs (NSAIDs): indomethacin, diclofenac, ketoprofen, piroxicam, tenoxicam and ketorolac. This index took into account both biopharmaceutic and pharmacodynamic aspects. The biopharmaceutic aspect, based on the maximal flux (J(m)), was determined experimentally from transdermal studies carried out with human skin in previous work. The pharmacodynamic aspect, based on the ability to inhibit cyclooxygenase-2 (COX-2) in vitro, was determined by incubating human dermal fibroblasts in culture, pre-treated with phobol-12-myristate-13-acetate (PMA) for 6 h, with 25 microM [(14)C]-arachidonic acid (AA) in the presence of several drug concentrations. The most potent inhibitor of COX-2 activity in induced fibroblasts was diclofenac while indomethacin, ketoprofen and ketorolac were approximately equipotent. Piroxicam and tenoxicam were inhibitors at higher concentrations. Based on the proposed index of the topical anti-inflammatory activity (ITAA) diclofenac, ketorolac, ketoprofen and indomethacin exhibited acceptable efficiency for external use. However, piroxicam and tenoxicam showed the lowest topical anti-inflammatory activity of the series assayed. In conclusion, indomethacin ketorolac, ketoprofen and diclofenac have shown good intrinsic feasibility for formulation into topical pharmaceutical forms. However, for dermatological formulations of oxicams, use of penetration enhancers may be unavoidable.

Influence of d-limonene on the transdermal penetration of felodipine

SummaryFelodipine is a calcium antagonist, one of the dihydropyridines, with potential application in transdermal therapeutic systems (TTS). Earlier studies reported that the high lag time of this drug limited its potential development in a TTS. The present study analyzes the effect of d-limonene at concentrations of 0.5, 1, 5 and 10% on the transdermal penetration of this drug. The study was performed using a diffusion technique in vitro, with the skin of the hairless rat. d-Limonene significantly reduced the lag time (T1) to 1.4 h at a concentration of 1% (compared with 9.8 h in its absence). Higher concentrations did not produce a significant decrease in the value of this parameter. The presence of d-limonene in the formulae produces an increase in the permeability constant (Kp) and the flux (J). The relation between this increase and the percentage of d-limonene was non-linear. An asymptotic value was obtained at a concentration of 5%, with increases of 993% and 1570% for Kp and J, respectively.

An experimental assessment of the Wagner-Sedman extraction theory for the intestinal absorption of antibacterial sulfonamides

The chromatographic parameters in a reverse-phase partition system and the rat gut in situabsorption rate constants for 18 antibacterial sulfonamides are highly correlated values. The correlation is logarithmic-logistic in nature, being in accordance with the Wagner-Sedman extraction theory for a constant pH value. Parabolic correlations did not satisfactorily fit the experimental data. This behavior, not frequently reported in regard to the intestinal absorption of drugs, is discussed in connection with other apparently contradictory available data.

Estimation of Transdermal Permeation Parameters in Non-stationary Diffusion Experiments. Application to Pre-treatment Studies with Terpenes

No HeadingPurpose.To estimate the applicability of transdermal drug permeation parameters in a finite-dose model for skin pre-treated with terpenes and to evaluate the enhancing effect of some terpene formulations on alprazolam permeation.Methods.In vitro enhancement of alprazolam human skin permeation was investigated using a pre-treatment with different terpene solutions. Vertical diffusion, Franz-type cells were used. Intrinsic drug permeation was also investigated. Transdermal permeation parameters were estimated from the per-meation tabulates using different theoretical approaches for their calculation. Two groups of permeation parameters were calculated: modelistic (diffusion of a finite-dose of drug model) and parameters non-dependent of a diffusional model.Results.In control experiments, all approaches of data treatment satisfactorily described the experimental permeation profiles. When skin pre-treatment was investigated, the fitting of a mathematical sigmoid function was much better than the diffusional approach. Pre-treatment of the skin with Limonene dissolved in ethanol / propylene glycol and Menthol dissolved in propylene glycol increased 15 and 10 times respectively the permeation parameters of alprazolam.Conclusions.Using enhancers that are rapidly cleared from the skin, skin permeability does not remain constant during the permeation experiment and therefore it is not possible to calculate parameters that are usually true coefficients or definite values. In this case, non-modelistic parameters can be used to estimate an enhancing effect.