T.M. Garrigues

Nortriptyline hydrochloride skin absorption: Development of a transdermal patch

The influence of propylen glycol (PG), ethanol, and oleic acid (OA) on nortriptyline hydrochloride (NTH) penetration through human epidermis was studied in vitro at two different pH values (5.5 and 7.4). The influence of lactic acid and polysorbate 80 was studied for a pH of 5.5. Permeation studies through Heat Separated Epidermis, as well as the enhancing effect of the different vehicles, showed a pH dependency. A pH value of 5.5 in the donor solution decreases significantly the permeability coefficient (Kp) with respect to a pH value of 7.4 (0.011+/-0.004 x 10(-6) versus 0.36+/-0.04 x 10(-6)cm/s). The vehicles showed an increasing enhancement effect in the order: polysorbate 80>ethanol/PG/OA>PG>ethanol>ethanol/lactic acid>lactic acid at pH 5.5 while they reduced the permeation of NTH at pH 7.4. Considering the results obtained at pH 5.5, the maximum enhancement ratios were found for polysorbate 80 and the combination ethanol/PG/OA (10.72 and 3.90). Both vehicles were selected for designing a NTH transdermal delivery system (NTH-TDS) using (hydroxypropyl)methyl-cellulose as polymer. The NTH-TDS based on the combination of ethanol/PG/OA showed an enhancement ratio with respect to control of 2.09 and the addition of polysorbate 80 to the matrix, of 5.82.

Compared effects of synthetic and natural bile acid surfactant on xenobiotic absorption. II: Studies with sodium glycocholate to confirm a hypothesis

Abstract The effects of sodium glycocholate (SGC) on the intestinal absorption of drug-related xeriobiotics are investigated, on the basis of previously established absorption/partition relationships. Six phenylalkylcarboxylic acids, closely related to nonsteroid anti-inflammatory drugs in structure and constituting a true homologous series, were used as test compounds through an in situ rat gut technique, using the whole colon as nonspecialized absorption membrane model. Whereas the synthetic surfactants (i.e., polysorbates and laurylsulphates) at the critical micelle concentration have been shown to disrupt the aqueous boundary layer adjacent to the membrane, SGC does not; in contrast, it reinforces its limiting effect on solute diffusion, thus leading to a poorer absorption of the compounds as their lipophilicity increases. On the other hand, at supramicellar concentrations, the micelle solubilizing effect of SGC for the compounds is incomparably lower than that found for synthetics, even in the presence of mixed micelles with lecithin. These results, in conjunction with previous observations, seem to indicate that as far as xenobiotic absorption is concerned, synthetics and natural bile acid surfactants behave as entirely different biopharmaceutical species.

Nortriptyline for smoking cessation: release and human skin diffusion from patches.

The objective of this work was to develop a simple and inexpensive transdermal formulation containing Nortriptyline Hydrochloride (NTH) for smoking cessation support therapy. Hydroxypropyl-methyl-cellulose was chosen as polymer and a mixture of transdermal enhancers (selected from previous research) was incorporated. The formulations were characterised in terms of appearance, thickness, uniformity of NTH content, release and skin permeation. Release studies demonstrated controlled release for four formulations. Diffusion studies were performed through human heat separated epidermis (HHSE) using Franz Diffusion Cells (FDC). Patches provided different fluxes varying from 20.39+/-7.09 microg/(cm(2) h) to 256.19+/-94.62 microg/(cm(2) h). The penetration profiles of NTH within the stratum corneum (SC) and deeper skin layers (DSL) were established after three administration periods (3 h, 6 h, and 24 h). Skin changes induced by the application of the patches were observed by confocal laser scanning microscopy (CLSM). The highest flux obtained would provide the recommended doses for smoke cessation support therapy (25-75 mg per day) with a 2 cm x 2 cm patch or a 3.5 cm x 3.5 cm patch, respectively, without skin damage evidence.

Absorption-partition relationships for true homologous series of xenobiotics as a possible approach to study mechanisms of surfactants in absorption. III. Aromatic amines and cationic surfactants

Abstract The previously proposed approaches for interpreting and quantifying the mechanisms elicited by nonionic surfactants on the intestinal and colonic absorption of 4-alkylanilines are extended here to the cationic surfactants dodecyltrimethylammonium bromide and tetradecyltrimethylammonium bromide. The effects of the cationics run parallel to those observed for nonionics and the only modification observed is a more effective membrane polarity increase, possibly inherent to their cationic nature. Therefore, the mechanisms involved in xenobiotic absorption modifications seem to be characteristic of the surfactants and independent of their ionization properties.

Compared effects of synthetic and natural bile acid surfactants on xenobiotic absorption. III. studies with mixed micelles

Abstract The present work deals with the effects of bile salts on absorption. It has previously been demonstrated that although they are surfactants, these salts are not able to disrupt the aqueous diffusion layer which effectively limits the absorption of the lipophilic compounds. They exhibit less ability less ability to solubilize in their micelles when they are perfused only in the presence of the tested compounds. The present study was carried out with two types of bile salts -sodium taurocholate and sodium glycocholate - along with other compounds naturally occurring in vivo, such as lecithin and sodium oleate. In this way the hypothesis that an intrinsic mechanism is involved in promoting the effect of bile salts on absorption was assessed by stimulating a physiological environment, which always shows mixed micelles of bile salts with phospholipids and fat. Correlations between absorption and lipophilicity parameters are useful for indirect quantification of this phenomenon. The enhancer effect of bile salts on the absorption of lipophilic compounds may be due to their effective absorption in the gut, which helps the disintegration of the micelles. Despite the fact that the characteristics of natural surfactants are not as good as those of synthetic surfactants for promoting absorption, a consideration of all their properties can explain all the features reported.

Correlation between in situ absorption and in vitro dialysis data found in the presence of surfactants

Abstract Dialysis rate constants of 4-alkylanilines in free solution ( k d ) are virtually the same as those found in the presence of polysorbate 80 at its critical micelle concentration ( k c ). In both cases, a dependence of molecular weight has been observed although the differences are very small. Such in vitro behaviour clearly differs from that found in in situ absorption experiments, where the influence of surfactant on the biological membrane and its environment leads to very dissimilar rate constant values in the absence and in the presence of surfactant at this concentration. A different picture is found when surfactant is present in the dialyzing solution at supramicellar concentration; dialysis rate constants ( k s ) decrease progressively as molecular weight and lipophilicity increase, due to micellar solubilization of the solutes. Fitting equations are analogous to those found for absorption studies. Free and micelle-solubilized amine fractions in situ are correlated with those found in vitro, so that the latter could be utilized for predictive purposes, thus helping to correctly design further in situ absorption studies.