Ion pair formation as a possible mechanism for the enhancement effect of lauric acid on the transdermal permeation of ondansetron.

Transdermal application can be an alternative drug delivery route for ondansetron, an antiemetic drug. Previous studies found that fatty acids, namely oleic and lauric, were the most effective penetration enhancers. The aim of this study was to investigate the formation of an ion pair between ondansetron and lauric acid as a possible mechanism of its enhancing action. Several techniques were used to reveal the formation of an ion pair complex. Partitioning experiments, where the n-octanol/water coefficient was measured, showed an increase in the distribution coefficient in the presence of the acid, possibly as a result of the formation of more lipophilic ion pairs between the charged molecules of ondansetron and lauric acid. Further evidence of complex formation between ondansetron and lauric acid, was gained from the 13C-nuclear magnetic resonance (13C-NMR) spectra of ondansetron, lauric acid, and their mixture (molar ratio 1:1). The NMR spectra revealed alterations to the magnetic environment of the carbon atoms adjacent to the ionized group, which are the carbonyl group of the acid and the nitrogen of the imidazole ring of ondansetron. This evidence substantiates the theory of ion pair formation. Finally, thermal analysis of the binary mixtures of ondansetron and lauric acid revealed the formation of an additional compound, with different melting point from pure ondansetron and lauric acid, which is thermodynamically favored.

Development and in vitro evaluation of furosemide transdermal formulations using experimental design techniques.

The in vitro skin permeation of furosemide, a commonly used loop diuretic, through human epidermis, as a preliminary step towards the development of a transdermal therapeutic system, was examined. A screening study was carried out, in order to estimate the effects of the type, the concentration of enhancer and the concentration of gelling agent on the cumulative amount of furosemide permeated through human epidermis, using a 3(3) factorial design. The type and the concentration of enhancer were further evaluated as they were found to affect significantly furosemide permeation. In order to further increase the amount of the drug permeated, the combination of two enhancers, Azone and oleyl alcohol, at three concentration levels was employed, using an optimization technique. The results indicated that higher amounts of furosemide permeated were observed when Azone was used at 5.0-6.5% (v/v) and oleyl alcohol at 7.5-9% (v/v), in the gels used. These formulations seem to be suitable for possible transdermal delivery of furosemide for pediatric use.

Use of an 8(1)3(2) asymmetrical factorial design for the in vitro evaluation of ondansetron permeation through human epidermis.

The in vitro permeation of ondansetron through human cadaver epidermis, as a preliminary step toward the development of a transdermal therapeutic system, was investigated. In vitro release studies were carried out using modified Franz diffusion cells and human epidermis, taken from cadaver skin by heat separation technique. To estimate the effect of the type and concentration of the penetration enhancers and the skin from different donors, an 8(1)3(2) asymmetrical factorial design was used. Formulations containing lauric acid and oleic acid as penetration enhancers, showed the largest Q values [amounts of ondansetron permeated per unit area of epidermal membrane (microg/cm2)] at 24, 48, and 72 hr, as well as steady-state flux values, among all formulations tested. The other enhancers increased the flux in the following order: lauryl alcohol>glycerol monooleate>Azone >cineole>oleyl alcohol>1-methyl-2-pyrrolidinone. Moreover, the concentration of the penetration enhancer and the type of the skin were proved to significantly affect the permeation rate of ondansetron through human epidermis. From the results obtained, it was shown that the formulations containing lauric acid or oleic acid at 5% or 10% could increase sufficiently the permeation of ondansetron. Therefore, the transdermal administration of ondansetron seems feasible.

Optimization of in vitro skin permeation by lactic acid from gel formulations.

The purpose of this study was to evaluate the effect of the concentration as well as the vehicle's pH on in vitro skin permeation by lactic acid from gel formulations, using an optimization technique. Nine gels containing 3%, 6%, and 9% (w/w) lactic acid in three different phosphate buffers, with pH values of 2.8, 3.8, and 4.8, were prepared and were applied in modified Franz diffusion cells. The pH of the vehicles and the lactic acid concentrations were used to create a mathematical model that correlates these factors with the cumulative amount of lactic acid permeated through human cadaver epidermis. For this purpose, the optimization technique 3(2) was applied. It was found that the correlation of the above factors can be adequately described with a polynomial equation, which can be used for predicting the cumulative amounts of lactic acid permeated. The results indicated that as the lactic acid's concentration increased, the cumulative amount permeated also increased after 24 h at all pH values. Moreover, the amount of lactic acid permeated decreased as the pH of the gels was increased. The greater amount permeated at all time intervals (6 h, 9 h, 12 h, and 24 h) was obtained when the concentration of lactic acid was 9% and the pH of the gel formulation was 2.8.