Membrane reservoir effect

In terms of the mechanisms of action, the pyrrolidones partition well into human horny layer. They may act by altering the solvent nature of the membrane and pyrrolidones have been used to generate reservoirs within skin membranes. Such a reservoir effect offers potential for sustained release of a permeant from the stratum corneum over extended time periods. However, as with many other potential enhancers, clinical use of pyrrolidones is problematic due to adverse reactions. An in vivo vasoconstrictor bioavailability study demonstrated that pyrrolidones caused erythema in some volunteers, although this effect was relatively short-lived. Also, a toxic hygroscopic contact reaction to NMP has been reported recently [21]. 

An ideal pharmacokinetic model of the percutaneous absorption process should be capable of describing not only the time course of penetration through skin and Into blood (or receptor fluid In a diffusion cell), but also the time course of disappearance from the skin surface and accumulation (reservoir effect) of penetrant within the skin membrane. Neither Pick s Plrst Law of Diffusion nor a simple kinetic model considering skin as a rate limiting membrane only Is satisfactory, since neither can account for an accumulation of penetrant within skin. To resolve this dilemma, we have analyzed the In vitro time course of absorption of radiolabeled benzoic acid (a rapid penetrant) and paraquat (a poor penetrant) through hairless mouse skin using a linear three compartment kinetic model (Figure 5). The three compartments correspond to the skin surface (where the Initial dose Is deposited), the skin Itself (considered as a separate compartment), and the receptor fluid In the diffusion cell. The Initial amount deposited on the skin surface Is symbolized by XIO, and K12 and K23 are first order rate constants. 

Fig. 3. Cumulative release provided by various release kinetics. A, Constant release, independent of time (zero order), such as that possible from a membrane reservoir device free of lag time or initial burst effects. B, Matrix or monolithic sphere with square root time release. C, First-order release A-zero order C-first order B-square root.

The hormone-releasing devices have a closer resemblance to standard methods of sustained release because they involve the release of a steroid compound by diffusion [198,199]. The Progestasert, a reservoir system, is shown in Fig. 16. Progesterone, the active ingredient, is dispersed in the inner reservoir, surrounded by an ethylene/vinyl acetate copolymer membrane. The release of progesterone from this system is maintained almost constant for 1 year. The effects of release are local, with none of the systematic side effects observed with orally administered contraceptives [200-207]. 

The point is also made [134] that the very high surface areas and the richly interconnected three-dimensional networks of these micron-sized spaces, coupled with periods of desiccation, could together have produced microenvironments rich in cat-alytically produced complex chemicals and possibly membrane-endosed vesides of bacterial size. These processes would provide the proximate concatenation of lipid vesicular precursors with the complex chemicals that would ultimately produce the autocatalytic and self-replicating chiral systems. A 2.5 km2 granite reef is estimated to contain possibly 1018 catalytic microreactors, open by diffusion to the dynamic reservoir of organic molecules. .. but protected from the dispersive effects of flow and convection [134] as well as protected from the high flux of ultraviolet radiation impinging on the early Earth. [123,137]... 

We summarize what is special with these prototype fast ion conductors with respect to transport and application. With their quasi-molten, partially filled cation sublattice, they can function similar to ion membranes in that they filter the mobile component ions in an applied electric field. In combination with an electron source (electrode), they can serve as component reservoirs. Considering the accuracy with which one can determine the electrical charge (10 s-10 6 A = 10 7 C 10-12mol (Zj = 1)), fast ionic conductors (solid electrolytes) can serve as very precise analytical tools. Solid state electrochemistry can be performed near room temperature, which is a great experimental advantage (e.g., for the study of the Hall-effect [J. Sohege, K. Funke (1984)] or the electrochemical Knudsen cell [N. Birks, H. Rickert (1963)]). The early volumes of the journal Solid State Ionics offer many pertinent applications. 

A system underpinned by commercially made screen-printed electrochemical cells was described by Palmisano et al. [19]. The cells were converted into biosensors for lactate in milk and yoghurt by addition of an electrochemically polymerised barrier to interference and a layer composed of lactate oxidase, glutaraldehyde and BSA. These steps appeared to have been carried out by hand. As there was no outer diffusion-limiting membrane, the linear range of the sensors was quite small (0-0.7 mM). They were incorporated into a FIA with a microdialysis unit based on a planar membrane and a buffer reservoir (earlier work used a microdialysis fibre with a platinum electrode [29]. The concentration of lactate was determined in various milks (0.27-1.64 mM), and in raw milk (c. 0.5-0.9 mM) left to degrade on the laboratory bench. The recovery of the microdialysis unit, 2.6%, implied that the sensor had an ability to return measurable currents for very low concentrations of lactate. A further implication is that the electro-polymerised layer was very effective at preventing interference. 

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