Drug delivery through the skin: molecular simulations of barrier lipids to design more effective noninvasive dermal and transdermal delivery systems for small molecules, biologics, and cosmetics

Human skin structure and effect of delivery systems and permeation enhancers on permeation of drug molecules. Three‐dimensional (3D) structure of human skin (left column): first‐generation approach to transdermal delivery is limited primarily by the barrier posed by skin's outermost layer called the stratum corneum, which is 10–20 µm thick. Underneath this layer is the viable epidermis, which measures 50–100 µm and is avascular. Deeper still is the dermis, which is 1–2 mm thick, and contains a rich capillary bed for systemic drug absorption and nerve endings just below the dermal–epidermal junction. Chemical permeation enhancers and drug delivery systems interact with the intercellular lipids in the stratum corneum. This interaction modifies the structural order of the lipids which are originally arranged in multiple bilayer stacks (left column) (electron micrograph and bilayer model: Reprinted with permission from Ref 16. Copyright 2006 Elsevier). This modification, fluidization, disorder, or rearrangement of the lipids can be monitored by small‐angle X‐ray scattering (SAXS)/wide‐angle X‐ray scattering (WAXS) (middle column). Conventional permeation enhancers such as ethanol, oleic acid, propylene glycol and a marketed enhancer, Transcutol, cause disordering of the lipids, but do not disrupt the bilayer configuration (right column). Among the lipid‐based delivery systems, liposomes and a submicron emulsion also have a disordering effect, whereas biphasic vesicles appear to cause rearrangement of the organization of the stratum corneum lipids into a Pn3m cubic phase configuration (SAXS pattern: middle column, model: right column). This cubic phase could be an intercellular permeation nanopathway that may explain the increased delivery of interferon‐α (IFN‐α) by biphasic vesicles.17

Synergistic feedback of computational simulations into predictive enhancement of the experimental observation of permeation enhancer effects. Using computational techniques it is possible to simulate the effects that drugs and penetration enhancers may have on components of the stratum corneum. Several parameters can be introduced and a predictive library can be constructed. This library can then be used to guide subsequent experimental design in an effort to eliminate unproductive results and speed combinatorial screening of large chemical libraries.

Construction of two ceramide bilayers separated by a thin layer of water. To observe the ability of a permeation enhancer to cross the stratum corneum and interactions at the intermembrane interface, a bilayer assembly was created using the CHARMM c33b1 package. To aid computational efficiency, a segment having a small cross‐sectional area of 50 × 50 Å was chosen. For the initial selection of the parameters required for ceramide equilibration, a ratio of 2:1 ceramide C15:0CER[NS] to cholesterol was used. These initial parameters produced an upper and lower bilayer containing 72 ceramide molecules (green sticks) and 36 cholesterol molecules (blue sticks) each. The two bilayers are separated by a 5 Å layer of water and are surrounded by a 12 Å layer of water on either side of the leaflet.

Schematic representation of the umbrella sampling technique. To perform umbrella sampling, one must first generate a series of configurations along a predetermined reaction coordinate. In this example, the reaction coordinate is defined by applying a constant force (y) to a permeation enhancer and pulling it through the (x, z) plane of a membrane composed of ceramides, cholesterol and free fatty acids (dashed arrow). Configurations generated in this way serve as the starting points for the umbrella sampling windows, which are run in independent simulations. Configurations of the system which are generated during the pulling step are extracted after the initial simulation is complete. The middle image corresponds to the independent simulations conducted within each sampling window, with the center of mass of the permeation enhancer restrained in that particular window by an umbrella biasing potential. The right panel illustrates an ideal histogram of configurations, with neighboring windows overlapping such that a continuous energy function with respect to the passage of the permeation enhancer through the bilayer can later be derived from these simulations.

An overview of skin permeation enhancer strategies. A representative flowchart illustrating several skin permeation enhancer strategies. Subcategories include stratum corneum (SC) bypass, SC manipulation, drug vehicle optimization, delivery systems, and combination approaches. Methods in bold under SC manipulation are also considered physical methods.

Application of small‐angle X‐ray scattering (SAXS)–wide‐angle X‐ray scattering (WAXS) for nanostructure analysis of stratum corneum lipids. Schematic (a) and experimental setup (b) of a SAXS measurement (enlarged picture shows the multisample holder developed in‐house for the stratum corneum samples); typical scattering pattern (c); and scattering curve of human stratum corneum (d).