Transdermal flux

Moody R. Automated in vitro dermal absorption (AIVDA) a new in vitro method for investigating transdermal flux. ALTA (Alternatives to Laboratory Animals) 1997 25 347-357. 

Many enhancers have a complex concentration-dependent effect. This is shown clearly by azone, which is effective in promoting the transdermal flux of many drugs when used at 1% in PG but which is far less potent when applied at higher concentrations or neat. 

Cormier M.J.N, Neukermans A.P, Block B, Theeuwes F.T, Amkraut A.A. Device and method for enhancing transdermal flux of agents being delivered or sampled. U.S. Patent 7,184,826, 2007. 

Tab. 4.12 Water solubilities, total transdermal fluxes, permeability coefficients, and differences between experimental and calculated IAM values for various compounds. (Reprinted from Tab. 2 of ref. 42 with permission from Elsevier Science)...

Finally, the coefficient of variation of the transdermal flux for one particular pharmaceutical, chlorpheniramine base, is compared within experiments and between experiments over a six month period. 

Occlusion of the skin, seen with application of water-impermeable drug vehicles or patches, alters the rate and extent of toxicant absorption. As the skin hydrates, a threshold is reached where transdermal flux dramatically increases (approximately 80% relative humidity). When the skin becomes fully hydrated under occlusive conditions, flux can be dramatically increased. This occlusive effect must be accounted for when extrapolating toxicology studies conducted under occlusive conditions to field scenarios where the ambient environmental conditions are present. Hydration may also markedly affect the pH of the skin, which varies between 4.2 and 7.3. Therefore, dose alone is often not a sufficient metric to describe topical doses when the method of application and surface area become controlling factors. Dose must be expressed as mg/cm2 of exposed skin. 

Stott, P.W. Wilhams, A.C. Barry, B.W. Characterization of complex coacervates of some tricyclic antidepressants and evaluation of their potential for enhancing transdermal flux. J. Controlled Release 1996, 41 (3), 2 5-221. 

The effect of formulation pH on skin permselec-tively has been clearly demonstrated " As the pH of a solution containing salicylate anion was increased from pH 4 to 6, and then to 8, the transdermal flux of salicylate anion at 200pA/cm decreased from 480 to 192, and then to 174pgh cm , respectively. 

Fentanyl (F) Female, full thickness Breast, abdomen F in aqueous solution or in patch, was applied on skin mounted to diffusion cell Transdermal flux No difference observed between test sites... 

Ashton P, Walters KA, Brain KR, Hadgraft J. Surfactant effects in percutaneous absorption. Part 1. Effects on the transdermal flux of methyl nicotinate. Int J Pharm 1992 87(10) 261—264. 

It must be stressed that both transdermal flux and Kp are not only chemical dependent but also tightly constrained by the membrane system studied as well as the experimental design of the study used to estimate it (neat compound, vehicle, length of experiment, etc.). The PC that is integral to Kp is the PC between the surface or applied vehicle and the stratum corneum lipids. Different vehicles will thus result in different PCs. Similarly skin from different species may result in different PC due to differences in the stratum corneum lipids and intercellular path lengths. From the computational toxicology perspective, this translates into quantitative models whose parameters are very dependent on experimental variables often not appreciated to be significant contributors to the process. 

Veterans also intentionally applied liberal amounts of the insect repellent DEET (V, V-diethyl-ffi-toluamide) to their skin surface. This repellent can cause acute severe neurotoxicity when applied in such large quantities. Compared to permethrin, DEET is a smaller molecule (MW = 191.27) and a smaller log octanol-water partition coefficient of 1.69. These features tend to favor significantly greater transdermal flux of DEET (63.2 pg/cm /h) (Ross and Shah, 2000). The oral LDjg in rats is 2170 to 3664 mg/kg its dermal LDjq is 5000 mg/kg in the same species, and it is in toxicity category III (U.S. EPA, 1998). 

These studies also determined that these various exposure conditions resulted in a wide range of DEET absorption (13 to 68 pg/cm ) within 8 h of dermal exposure. It should be noted that DEET absorption ranged from 13 to 16 pg/cm irrespective of whether it is either 7.5 or 75% DEET in a binary ethanol mixture. In effect, DEET transdermal flux is a zero-order kinetic process with a flux of 2.0 pg/cm /h. This transdermal flux was also observed in human skin exposed to either neat or 15% DEET (Selim etal., 1995) and demonstrates that DEET flux is saturated... 

The last level of potential interaction is in the dermis, where a component chemical may directly or indirectly (e.g., via cytokine release in the epidermis) modulate vascular uptake of the penetrated toxicant (Riviere and Williams, 1992 Williams and Riviere, 1993). In addition to modulating transdermal flux of chemical, such vascular modulation could also affect the depth and extent of toxicant penetration into underlying tissues. 

The results show that the reduction in the melting temperature of testosterone by 114°C, accompanied by an elevation in its solubility, brought about an increase in the transdermal flux of the drug through skin and silastic membrane. In permeation experiments of testosterone from... 

However, the transdermal flux of medically useful peptides and proteins is often insufficient to be therapeutically effective due to the large molecular weight. 

Figure 8. Transdermal flux of monomeric insulins during in vitro iontophoresis (cathodal...

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