High-efficient nano-carrier gel systems for testosterone propionate skin delivery.

The purpose of the current investigation was to evaluate the skin delivery potential of the different nano-carrier gels including liposomal gel, ethosomal gel and microemulsion gel bearing testosterone propionate (TP) as a testosterone deficient therapy. The prepared nano-particles were characterized for their shape, particle size distribution and zeta potential. In vitro skin permeation and in vivo transdermal delivery of nano-carrier gels were studied with the Franz diffusion cells and confocal laser scanning microscopy (CLSM). The results showed that all of nano-particles were almost spherical with low polydispersity and nano-metric size range from 40 to 200 nm. TP ethosomal gel also provided an enhanced transdermal flux of 7.64 ± 1.4 µg/cm(2)/h and a decreased lag time of 0.69 h across rat skin as compared with the other two formulations. The skin penetration efficiency of TP nano-carrier gels also revealed that TP ethosomal gel would enhanced penetration of rhodamine red (RR)-loaded formulation to the deeper layers of the skin (268 µm) than the liposomal gel (192 µm) and microemulsion gel (228 µm). This study demonstrated TP ethosomal gel is a promising nano-carrier for delivering TP through the skin.

Enhanced transdermal bioavailability of testosterone propionate via surfactant-modified ethosomes.

The current investigation aimed to evaluate the transdermal potential of novel testosterone propionate (TP) ethosomes and liposomes prepared by surfactant modification. The effect of hexadecyl trimethyl ammonium bromide and cremophor EL-35 on the particle size and zeta potential of the prepared vesicles was investigated. The entrapment efficiency and stability, as well as in vitro and in vivo skin permeation, were studied with the various techniques, such as differential scanning calorimetry, confocal laser scanning microscopy, transmission electron microscopy, dynamic light scattering, and so on. The results indicated that the ethosomes were defined as spherical, unilamellar structures with low polydispersity (0.100 ± 0.015) and nanometric size (156.5 ± 3.5 nm). The entrapment efficiency of TP in ethosomal and liposomal carriers was 92.7% ± 3.7% and 64.7% ± 2.1%, respectively. The stability profile of the prepared TP ethosomal system assessed for 120 days revealed very low aggregation and very low growth in vesicular size. TP ethosomes also provided an enhanced transdermal flux of 37.85 ± 2.8 µg/cm(2)/hour and a decreased lag time of 0.18 hours across mouse skin. The skin permeation efficiency of the TP ethosomes as further assessed by confocal laser scanning microscopy revealed enhanced permeation of rhodamine red-loaded formulations to the deeper layers of the skin (260 µm) than that of the liposomal formation (120 µm).

Enhanced rat Hershberger assay appears reliable for detection of not only (anti-)androgenic chemicals but also thyroid hormone modulators.

Development of an internationally recognized standard for the Hershberger assay as a screening tool to detect potential (anti-)androgenic chemicals is in progress. In the present preliminary study, we evaluated the reliability of the enhanced Hershberger assay to detect thyroid hormone modulating activity, while concentrating attention on possible confounding influence on evaluation of (anti-)androgenic activity. Castrated or testosterone propionate (TP; 0.2 or 0.25 mg/kg/day)-injected castrated male Crj:CD(SD) IGS rats (seven weeks of age) were dosed for 10 days by oral gavage with vehicle (corn oil) or the following chemicals: propylthiouracil (PTU; 2.5 mg/kg/day), a potent inhibitor of thyroid hormone synthesis, phenobarbital (PB; 125 mg/kg/day) and 2,2-bis(4-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE; 100 mg/kg/day), two hepatic enzyme inducers that enhance the clearance of thyroid hormones. PTU markedly increased thyroid weights, and decreased serum T3 and T4, and increased serum TSH, also causing marked microscopic alteration of the thyroid gland. In comparison, PB and p,p'-DDE only significantly affect serum T4 and revealed some histopathological findings. The alterations appeared to be more robust in the presence of TP. Furthermore, data for p,p'-DDE demonstrated its anti-androgenic effects, whereas PTU and PB had little or no effects on the weights of androgen-related accessory glands/tissues: the ventral prostate, dorso-lateral prostate, seminal vesicles with coagulating glands, glans penis, Cowper's glands, and levator ani plus bulbocavernosus (LABC) muscles. Weight of the LABC muscles was decreased by PB treatment in TP-treated castrated rats. These findings in the present study suggests that the enhanced Hershberger assay, with evaluation of thyroid histopathology and weights, and hormone levels, appears to be reliable for screening for not only (anti-)androgenic chemicals but also thyroid hormone modulators. In order to evaluate whether the sensitivity and specificity of such a thyroid assay is great enough for routine screening purposes, future experiments including dose-response studies using lower dose levels have to be performed.

Testosterone undecanoate: a useful tool for testosterone administration in rats.

A major obstacle of testosterone (T) treatment in experimental animals is the difficulty of maintaining long-term physiologic/anabolic steady serum levels after exogenous T administration. In two complementary studies we investigated the pharmacokinetic properties of different T formulations in male rats. Study I. Mature male Wistar rats (> 380 g, n = 4 - 7/group) were divided into four treatment groups: (1) sham-operated non orchiectomised (non-ORX) and placebo; (2) orchiectomised (ORX) and subcutaneous testosterone pellets (TP) (15, 25, 75 mg/60 days release or placebo pellets); (3) ORX and a single injection of testosterone undecanoate (TUD) (31, 62.5 or 125 mg/kg body weight subcutaneously (s.c.) or vehicle; (4) ORX and testosterone propionate (Tprop) (10, 20, 40 mg/month) or vehicle as a single injection s.c. Serum T was measured at baseline and in weekly intervals for 4 weeks. Study II. Mature male Wistar rats (180 - 200 g) were randomly assigned to one of 5 experimental groups (n = 5 - 6/group): (1) normal untreated rats (controls); (2) ORX untreated rats, and non-ORX rats receiving one of three treatment options; (3) 250 mg/kg body weight TUD i.m. (TUD 250); (4) 500 mg/kg body weight TUD i.m. (TUD 500); (5) 100-mg testosterone pellet/90 days release s.c. (TP 100). Serum T was measured at baseline and in intervals for 6 weeks after T administration. In both studies, the kinetic profile of TUD showed favourable continuous steady state levels over several weeks. In contrast, testosterone release by subcutaneous pellets resulted in a shorter than expected duration of elevated serum T levels with high inter-individual variability. Tprop administration led to only a short-lasting serum T increase with low serum T levels already 14 days after injection. In conclusion, a single injection of TUD (100 mg/kg body weight s.c.) is effective in inducing physiological testosterone levels in ORX rats for a minimum of four weeks. High dose TUD (500 mg/kg body weight i.m.) given as a single injection results in supraphysiological anabolic testosterone concentrations for up to six weeks in non-ORX rats. TUD was superior to other T release preparations and represents a convenient and effective tool for T administration in experimental animals.