The role of vehicle interactions on permeation of an active through model membranes and human skin

Abstract

Previous work from this group has focused on the molecular mechanism of alcohol interaction with model membranes, by conducting thermodynamic and kinetic analyses of alcohol uptake, membrane partitioning and transport studies of a model compound (i.e. methyl paraben) in silicone membranes. In this article, similar membrane transport and partitioning studies were conducted in silicone membranes to further extend the proposed model of alcohol interactions with silicone membranes to include other vehicles more commonly used in dermal formulations, that is, isopropyl myristate (IPM), dimethyl isosorbide (DMI), polyethylene glycol (PEG) 200, PEG 400 and Transcutol P® (TC). More importantly, membrane partitioning studies were conducted using human SC to evaluate the application of the proposed model of solvent-enhanced permeation in simple model membranes for the more complex biological tissue. The findings support a model of vehicle interactions with model membranes and skin where high solvent uptake promotes drug partitioning (i.e. K) by enabling the solute to exist within the solvent fraction/solvent-rich areas inside the membrane or skin in a concentration equivalent to that in the bulk solvent/vehicle. High solvent sorption may also ultimately impact on the membrane diffusional characteristics, and thus the diffusion coefficient of the solute across the membrane. The implications for skin transport are that increased partitioning of a drug into the SC may be achieved by (i) selecting vehicles that are highly taken up by the skin and also (ii) by having a relatively high concentration (i.e. molar fraction) of the drug in the vehicle. It follows that, in cases where significant co-transport of the solvent into and across the skin may occur, its depletion from the formulation and ultimately from the skin may lead to drug crystallization, thus affecting dermal absorption.

In vitro skin models as a tool in optimization of drug formulation

“…The use of isolated epidermis or SC sheets from human or animal origin has a number of disadvantages such as high intra-and inter-individual variations, in particular related to diseased skin for which most of the topical drug formulations are developed. The simplified artificial model membranes that could offer a simple and reproducible alternative to study the basic physicochemical mechanisms of drug permeation are preferred to understand the physicochemical determinants of vehicle-membrane interactions crucial for the selection of the optimal penetration enhancers and effective formulation design Oliveira et al, 2012). The artificial model membranes are thus enabling the testing and evaluation of various drugs and drug formulations as an initial screening approach to narrow the selection of the formulations to be evaluated with a more biologically intact model, thereby improving the efficiency in the optimization of new topical formulations.…”

Dermal and Transdermal Delivery of Active Substances from Semisolid Bases

“…The composition of the semisolid base impacts parameters of the active substance that are important from the point of view of the release, skin and transdermal delivery such as: concentration of dissolved form, thermodynamic activity, skin/base partition coefficient as well as diffusion coefficient in stratum corneum (skin permeability) [2,[15][16][17][18][19] . The values of these parameters should be as high as possible to maximize the rate of release and skin and transdermal delivery [2,[15][16][17][18][19] .…”

“…PEGs penetration into the skin is very poor due to their highly hydrophilic nature [18] . Poor penetration of PEGs into the skin as well as their solubilizing capacities may contribute to decrease in the value of skin/base partition coefficient of substances dissolved in PEG ointments and thus decrease in skin penetration.…”

“…The release of active substances from hydrophilic emulsions is usually higher than from hydrophobic emulsions. The emulsifiers, especially these with high HLB values, may increase the penetration of acceptor fluid into the emulsion base [18] .…”

“…The impact of semi-solid base components on the skin, in particular on the stratum corneum, includes: hydration and incorporation of some semisolid base components into the intercellular cement lipids leading to increased disordering of lamellar and lateral packing of lipids and/or increased solubility of the active substance within the stratum corneum lipids [4,16,18] . These interactions may alter the stratum corneum permeability (influence on skin penetration and permeation rate) or change the value of skin/base partition coefficient (influence on the rate of the skin retention) [16] .…”