Vehicles skin absorption rate

The elimination of [i C]triethanolamine from the blood of mice administered 1.0 mg/kg bw intravenously showed first-order biphasic kinetics with a rapid (0.58-h half-life) and a slow phase (10.2-h half-life). The slow phase half-lives for elimination of triethanolamine in mice after dermal exposure to 1000 and 2000 mg/kg bw in acetone were 9.7 h and 18.6 h. Skin absorption rates (as blood concentration-time curves) after dermal application of aqueous and neat [I CJtriethanolamine to mouse skin (2000 mg/kg bw, enclosed by a glass ring) showed no significant change with the use of water as the vehicle (Waechter Rick, 1988, cited in Knaak et al, 1997). 

Percutaneous penetration of 7V-nitrosodiethanolamine was measured using cryo-preserved human trunk skin and three vehicle formulations (isopropyl myristate, sunscreen cream or a 10% shampoo) containing 7V-nitroso[ C]diethanolamine. The absorption rate of a low dermal dose (10 ixg/cm ) of 7V-nitrosodiethanolamine was a linear function of the concentration (0.06, 0.2 or 0.6 Xg/ xL) applied to the skin. The peak rates for the isopropyl m uistate and shampoo vehicles were seen within five hours and for the sunscreen somewhat later. Total 48-h absorption ranged from 35 to 65% of the dose and was formulation-dependent (isopropyl m uistate > shampoo > sunscreen). A total absorption of 4-6 x JcaE was estimated to equate to an applied N-nitrosodiethanolamine dose of 10 x%lcaE. When applied as a large infinite dose (0.5 mg/cm ), total 7V-nitrosodiethanolamine absorption (4-35% of the applied dose) followed a different rank order (shampoo > isopropyl m uistate > sunscreen), probably due to the barrier-damaging properties of the vehicles. The permeability coefficient for isopropyl myristate was 3.5 X 10 cm/h (Franz etal., 1993). 

Absorption of substances from outside the skin to positions beneath the skin, including entrance into the blood stream, is referred to as percutaneous absorption. This is shovm in Figure 2.5. The absorption of a medicament present in a dermatological such as a liquid, gel, ointment, cream, paste, among others depends not only on the physical and chemical properties of the medicament but also on its behavior in the vehicle in which it is placed and upon the skin conditions. The vehicle influences the rate and degree of penetration, which varies with different drugs and vehicles. 

It is important to conduct a study in a way that most closely simulates normal exposure to the compoimd of interest. The length of exposure of a compound in contact with the skin is often assumed to be 24 h unless it is washed off more quickly, such as occurs with a shampoo or hair color. Because the vehicle can play a major role in determiiung the absorption rate, the vehicle used in the absorption smdy should be similar to that foimd in normal exposure conditions. 

The parameter a = kJ ID is the ratio of the rate of chemical transfer from the soil to the SC (a process that can be characterized by a mass transfer coefficient which has units of cm s ) to the rate of mass transport through the SC (i.e., DIL). Thus, when a > 1, the SC resistance is most important on the other hand, for a < 1, mass transfer from the soil to the SC limits the dermal absorption rate. When the mass transfer resistance from the vehicle is insignificant, the concentration of chemical on the skin surface (i.e., C ) is equal to (see Equation 11.2). By comparison, when the mass transfer resistance witliin the vehicle is not small relative to that in the SC (i.e., a is not very large), then at steady state is reduced relative to as specified by Equation 11.3. That is. 

Sorbitan sesquioleate emulsions of petrolatum and wax are used as ointment vehicles in skin treatment. In topical appHcations, the inclusion of both sorbitan fatty esters and their poly(oxyethylene) derivatives modifies the rate of release and promotes the absorption of antibiotics, antiseptics, local anesthetics, vasoconstrictors, and other medications from suppositories, ointments, and lotions. Poly(oxyethylene(20)) sorbitan monooleate, also known as Polysorbate 80 (USP 23), has been used to promote absorption of ingested fats from the intestine (245). 

Parameters Controlling Absorption. The absorption of a chemical into the skin is a function of the nature of the molecule, the behavior of the vehicle, and the status of the skin. Three major variables account for differences in the rate of absorption or flux of different topical chemicals or of the same molecule in different vehicles the concentration of the molecule in the vehicle, the partition coefficient of chemical between the stratum comeum and the vehicle, and the diffusion coefficient of molecule in the stratum comeum (Garner and Matthews, 1998). 

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. 

The rate of absorption is influenced by the status of the skin, chemical structure of the steroid and such other factors as formulation and formulation vehicle. Topical corticoids applied to diseased skin will be absorbed to some degree into the systemic circulation. When administration is chronic or when large areas of skin are involved, the absorption may be sufficient to cause systemic effects including cushinoid changes and adrenocortical suppression. 

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