Skin Permeation of Testosterone and its Ester Derivatives in Rats

Abstract

To establish the optimum conditions for improving the transdermal delivery of testosterone, we studied the relationship between the lipophilicity of testosterone ester derivatives and the rat skin permeation rate of testosterone. We performed a rat skin permeation study of testosterone and its commercially available ester derivatives, testosterone hemisuccinate, testosterone propionate and testosterone-17beta-cypionate, using an ethanol/water co-solvent system. The aqueous solubility and rat skin permeation rate of each drug, saturated in various compositions of an ethanol/water system, was determined at 37 degrees C. The aqueous solubility of testosterone and its ester derivatives increased exponentially as the volume fraction of ethanol increased up to 100% (v/v). The stability of testosterone propionate in both the skin homogenate and the extract was investigated to observe the enzymatic degradation during the skin permeation process. Testosterone propionate was found to be stable in the isotonic buffer solution and in the epidermis-side extract for 10h at 37 degrees C. However, in the skin homogenate and the dermis-side extract testosterone propionate rapidly degraded producing testosterone, implying that testosterone propionate rapidly degraded to testosterone during the skin permeation process. The steady-state permeation rates of testosterone in the ethanol/water systems increased exponentially as the volume fraction of ethanol increased, reaching the maximum value (2.69+/-0.69 microg cm(-2)h(-1)) at 70% (v/v) ethanol in water, and then decreasing with further increases in the ethanol volume fraction. However, in the skin permeation study with testosterone esters saturated in 70% (v/v) ethanol in water system, testosterone esters were hardly detected in the receptor solution, probably due to the rapid degradation to testosterone during the skin permeation process. Moreover, a parabolic relationship was observed between the permeation rate of testosterone and the log P values of ester derivatives. Maximum flux was achieved at a log P value of around 3 which corresponded to that of testosterone (log P = 3.4). The results showed that the skin permeation rate of testosterone and its ester derivatives was maximized when these compounds were saturated in a 70% ethanolic solution. It was also found that a log P value of around 3 is suitable for the skin permeation of testosterone related compounds.

A combined approach of chemical enhancers and sonophoresis for the transdermal delivery of tizanidine hydrochloride

“…Ethanol used as part of a co-solvent system has been observed to increase the permeation of a wide range of drugs through human and animal skin (Parikh and Ghosh, 2005;Garner et al, 2007). Low concentrations of ethanol reportedly alter the properties of the lipid component and at higher concentrations new pores are formed in the stratum corneum (Kim et al, 2000). In the present study, the flux of TIZ was increased as the concentration of ethanol was increased up to 60% v/v.…”

“…A solubility study was conducted to select a suitable receptor media for TIZ according to the procedure described by Kim et al (2000). An excess amount of drug was added to different aqueous systems and the mixture was placed on an agitating water bath for 24 hr at room temperature.…”

“…The in vitro skin degradation of TIZ was investigated in epidermis, dermis, and skin extracts following the method reported by Kim et al (2000). Briefly, freshly excised mouse skin was mounted between the two halves of a diffusion cell, with stratum corneum facing the donor half-cell and the dermis facing the receptor half-cell.…”

“…The corresponding flux values were found in the following order: Ethanol 10% < Ethanol 20% < Ethanol 40%* < Ethanol 50%* < Ethanol 60%* > Ethanol 80%* (* indicates significant difference compared to control, p < 0.05). Ethanol is one of the most commonly used skin permeation enhancers (Kim et al, 2000). Ethanol used as part of a co-solvent system has been observed to increase the permeation of a wide range of drugs through human and animal skin (Parikh and Ghosh, 2005;Garner et al, 2007).…”

Usefulness of Rat Skin as a Substitute for Human Skin in the in Vitro Skin Permeation Study

“…The advantages of these animals are their small size and easy handling. Sprague-Dawley (SD) rats are broadly used for in vivo pharmacokinetic, pharmacological, and toxicological studies as parts of preclinical studies for drug development [14,15,19,32,35]. SD rats as well as hairless rats are often used for in vivo percutaneous absorption and in vitro skin permeation studies.…”