Permeation Of Testosterone Research Articles

Solvent and Crystallization Effects on the Dermal Absorption of Hydrophilic and Lipophilic Compounds

This study probes the mechanisms by which volatile solvents (water, ethanol) and a nonionic surfactant (Triton X-100) influence the skin permeation of dissolved solutes following deposition of small doses onto unoccluded human skin. A secondary objective was to sharpen guidelines for the use of these and other simple solvent systems for dermal safety testing of cosmetic ingredients at finite doses. Four solutes were studied – niacinamide, caffeine, testosterone and geraniol – at doses close to that estimated to saturate the upper layers of the stratum corneum. Methods included tensiometry, visualization of spreading on skin, polarized light microscopy and in vitro permeation testing using radiolabeled solutes. Ethanol, aqueous ethanol and dilute aqueous Triton solutions all yielded surface tensions below 36 mN/m, allowing them to spread easily on the skin, unlike water (72.4 mN/m) which did not spread. Deposition onto skin of niacinamide (32 μg·cm−2) or caffeine (3.2 μg·cm−2) from water and ethanol led to crystalline deposits on the skin surface, whereas the same amounts applied from aqueous ethanol and 2 % Triton did not. Skin permeation of these compounds was inversely correlated to the extent of crystallization. A separate study with caffeine showed the absence of a dose-related skin permeability increase with Triton. Permeation of testosterone (8.2 μg·cm−2) was modestly increased when dosed from aqueous ethanol versus ethanol. Permeation of geraniol (2.9 μg·cm−2) followed the order aqueous ethanol > water ∼ 2 % Triton >> ethanol and was inversely correlated with evaporative loss. We conclude that, under the conditions tested, aqueous ethanol and Triton serve primarily as deposition aids and do not substantially disrupt stratum corneum lipids. Implications for the design of in vitro skin permeability tests are discussed.

Increased cutaneous absorption reflects impaired barrier function of reconstructed skin models mimicking keratinisation disorders

The aim of this study was to assess a recently established 3D model of congenital ichthyosis, representing severe epidermal barrier function defects, for skin penetration and permeation. We have generated disease models by knock-down of either TGM1 or ALOXE3 in primary human keratinocytes, and using keratinocytes and fibroblasts from patients with congenital ichthyosis. The results indicate disturbed barrier function as demonstrated by increased permeation of testosterone and caffeine particularly in TGM1 knock-down models compared to control models. In addition, enhanced penetration of the model dye nile red incorporated into solid lipid nanoparticles and core-multishell nanotransporters, respectively, was evident in disease models. Thus, in vitro skin disease models reproduce differences in barrier permeability and function seen in congenital ichthyosis and pave the way to personalised disease models. Furthermore, our findings indicate that nanocarriers may be useful in new, topical therapeutic approaches for the currently very limited treatment of congenital ichthyosis.

The Phenion® Full-Thickness Skin Model for Percutaneous Absorption Testing

In recent years many efforts have been made to replace dermal toxicity testing of chemicals in the animal by in vitro assays. As a member of a German research consortium, we have previously contributed to the validation of an in vitro test protocol for percutaneous absorption studies on the basis of reconstructed human epidermis and both human and pig skin ex vivo. Aiming to assess the barrier properties of a newly developed reconstructed skin model, this protocol has now been transferred to the Phenion® Full-Thickness Skin Model (FT model). The permeation of testosterone and caffeine was quantified in parallel to that of pig skin using Franz-type diffusion cells. In addition, the permeation of benzoic acid and nicotine was studied. As expected, the FT model is more permeable than pig skin, yet its barrier properties are well in accordance with those of reconstructed human epidermis when compared to previous data. In fact, the FT model most efficiently retards testosterone as the compound of highest lipophilicity, which can be explained by an additional uptake by a reservoir formed by the dermis equivalent. Thus, the structure closely parallels human skin. In consequence, the Phenion FT model appears to be suitable for percutaneous absorption studies in hazard analysis and should be subjected to a catch-up validation study.

Synergic enhancing-effect of DEET and dodecylamine on the skin permeation of testosterone from a matrix-type transdermal delivery system

The synergic in vitro skin permeation enhancing-effect of N,N-diethyl-m-toluamide (DEET) and dodecylamine was investigated in order to develop a novel non-scrotal matrix-type transdermal delivery system of testosterone (TS). When DEET was loaded in DuroTak® 87-2510 together with 2% TS and 3% dodecylamine, the in vitro rat skin permeation rate of TS synergistically increased as DEET concentration increased up to 0.5%. No further increase in permeation was observed thereafter and a plateau was observed up to 3.8% DEET. Moreover, compared to 0.5% DEET concentration, the addition of 3.8% of DEET in combination with 3% dodecylamine and 6% TS further increased the permeation rate of TS, and the maximum permeation rate of 11.21 μg/cm2/h was achieved. The in vitro skin permeation rates of TS from a transdermal delivery system of DuroTak® 87-2510 containing 6% TS, 3% dodecyamine, and 3.8% DEET were in the following order: hairless mouse skin > rat skin > human cadaver skin. Assuming that a system with a surface area of 60 cm2 is applied, the human cadaver skin permeation rate of 5.74 μg/cm2/h achieved in this study can be interpreted as being equivalent to delivering ∼ 8. 27 mg of TS per day. Considering that the commercially available product (Testoderm®TTS) for non-scrotal skin of the same surface area is designed to administer 5 mg of TS per day, the new formulation could maintain therapeutic plasma concentration of TS at a smaller surface area of 40 cm2.

Effect of Sonophoresis and Chemical Enhancers on Testosterone Transdermal Delivery from Solid Lipid Microparticles: An In Vitro Study

The main objective of the study was to investigate the effect of permeation enhancers and application of low frequency (LUS) and high frequency ultrasound (HUS) on testosterone (TS) transdermal permeation after application of testosterone solid lipid microparticles (SLM). SLM formulations contained 10% compritol and 5 mg TS /g of SLM. The permeation experiments were performed using Franz diffusion cells and abdomen rat skin. The examined permeation enhancers were 1% oleic acid (OA) or 1 % dodecylamine (DA). HUS (1 MHz) was applied in a continuous mode for 1h at intensity 0.5 W/cm(2). Different intensities and application time of pulsed LUS (20 kHz) were also examined. Additionally, the effect of combination of US and OA or DA was investigated. Skin irritation and histological changes were also evaluated. The results revealed that SLMs have an occlusive effect on the skin. Statistical analysis revealed the following order for the permeation of TS: 1% DA for 30 min>HUS +1% DA for 30 min= HUS=HUS + SLM containing 1% OA> SLM containing 1% OA=control. At total application time of LUS 6, 12, and 15 min the flux increased by 1.86, 4.63, and 4.77 fold, respectively. The enhancement effect of different intensities of LUS was not directly proportional to the magnitude of intensity. Skin exposure to HUS or LUS before application of 1% DA for 30 min had no superior enhancement effect over application of either LUS or HUS alone. Application of drug loaded SLM offered skin protection against the irritation effect produced by TS and 1% DA. Histological characteristics of the skin were affected to various extents by application of enhancers or ultrasound. In general, application of LUS gave higher TS permeation than HUS. However, safe application of LUS should be practiced by careful selection of exposure parameters.

In vitro and In vivo Evaluation of Novel Gel Formulations of Testosterone for Transdermal Delivery

HPMC-based novel gel formulations for the transdermal delivery of testosterone (TS) were developed, and the effect of various skin permeation enhancers was studied in vitro and in vivo. In vitro hairless mouse skin permeation of TS from the gel was investigated using Keshary-Chien diffusion cells for 8 hours at . In vivo plasma concentration profiles of TS after applying the gel on the abdominal skin of rat were determined using a commercial radioimmunoassay kit. Hairless mouse skin permeation of TS increased with the addition of permeation enhancers both in vitro and in vivo. Combination of diethanolamine (2%) and N-methylpyrrolidone (NMP, 6%) was the most effective among tested. Plasma concentration of TS significantly increased for at least 24 hours with the addition of diethanolamine and NMP. These results suggest the feasibility of the development of a HPMC-based gel formulation for the transdermal delivery of TS.

Synergistic enhancement of testosterone transdermal delivery

In this study, the effects of occlusion, octisalate (OS), and propylene glycol (PG) on the in vitro skin permeability of testosterone (TES) have been investigated. TES (either alone or with OS 5% w/v) was applied as a finite dose to full-thickness neonatal porcine skin mounted in flow-through diffusion cells and the amount of TES appearing in the receptor solution (20% v/v ethanol) was determined over 24 h. The skin was occluded with a microscope glass cover slip and to determine the effect of PG, 400 μl of PG/water mixtures (of varying PG concentration) was applied. In addition, the effect of Solugel™ (a proprietary hydrogel containing PG 25% w/w) and Tegaderm™ (a semipermeable film dressing) on the permeation of TES was assessed. Occlusion had no effect on the permeation of TES, however, OS increased the flux of TES 2.9-fold. The concentration of PG which produced optimal TES flux was 20% v/v, and this concentration resulted in a 1.9-fold increase in TES permeation. By combining OS, PG, and occlusion, TES permeation was increased 8.7-fold, which was a synergistic enhancement. In addition, Solugel™ and Tegaderm™, when applied to the skin, produced a similar enhancement in TES permeation to that produced by PG 25% w/w and occlusion.

The Effects of Pressure-Sensitive Adhesives and Solubilizers on the Skin Permeation of Testosterone from a Matrix-Type Transdermal Delivery System

ABSTRACTMatrix-type transdermal delivery systems of testosterone (TS) were formulated with three different pressure-sensitive adhesives (PSA). The effects of PSA, skin permeation enhancers, and solubilizers on the rat skin permeation rate of TS were systematically investigated. Without a solubilizer, the skin permeation rate of TS reached its maximum value when only 2% of TS was loaded in the matrix and the crystal formation in the matrix was very rapid and severe. Two surfactants differing in their hydrophile–lipophile balance (HLB) number were, therefore, considered. Span 80, which was of the lower HLB number, was more effective than Tween 80 in increasing the solubility, and thereby increasing the permeation rate of TS. Moreover, the concentrations of both the solubilizer and the skin permeation enhancer affected the skin permeation rate. Thus, the highest skin permeation rate (4.14 µg/cm2/hr) was achieved when 2% TS was loaded in DuroTak® 87-2516 together with 10% Span 80 and 3% dodecylamine, the permeation enhancer. In vivo study showed that the application of an experimental patch on rat abdominal skin resulted in a prompt and significantly higher plasma concentration of TS than that of a commercial product (Testoderm®) designed to apply on the scrotal skin. The area under the curve (AUC) increased linearly as the loading dose of TS increased up to 6%. Thus, based on these results, a non-scrotal matrix-type transdermal delivery system of TS could be developed.

A method for the determination of cellular permeability coefficients and aqueous boundary layer thickness in monolayers of intestinal epithelial ( Caco-2) cells grown in permeable filter chambers

A linear relationship between apparent permeability coefficients ( P app) and agitation rate was used to determine cell permeability coefficients ( P c) and the thickness of the aqueous boundary layer ( h aq) in monolayers of Caco-2 cells. Drugs with different physical/chemical properties were studied. P app values for ‘highly permeable drugs’ (testosterone, corticosterone, propranolol, metoprolol, warfarin) were dependent on the agitation rate, i.e. on the h aq. The permeation of testosterone was studied in detail. In the absence of agitation, the measured P app value of testosterone was 35.7 ± 3.3 × 10 −63 cm/s while the P c value was 137.4 ± 8.1 X 10 −6 cm/s, i.e. 3.8 times higher. P app values for ‘less permeable drugs’ (hydrocortisone, salicylic acid, sulphasalazine, mannitol) were not dependent on the agitation conditions. In the absence of agitation, h aq for testosterone was 1544 ± 142 μm and the contribution of the resistance of the aqueous boundary layer to the total diffusional resistance was 70%. h aq was reduced to 128 + 10 μm when the highest agitation rate was used. Under these conditions, the contributions of the resistances of the aqueous boundary layer and the Caco-2 cell monolayers were 16 and 73%, respectively. Similar results were obtained for the other highly permeable drugs. The results indicate that the P app values for highly permeable drugs are controlled not only by the aqueous boundary layer but also by the Caco-2 cell monolayers.