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WIREs Nanomed Nanobiotechnol
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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

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The delivery of drugs through the skin provides a convenient route of administration that is often preferable to injection because it is noninvasive and can typically be self‐administered. These two factors alone result in a significant reduction of medical complications and improvement in patient compliance. Unfortunately, a significant obstacle to dermal and transdermal drug delivery alike is the resilient barrier that the epidermal layers of the skin, primarily the stratum corneum, presents for the diffusion of exogenous chemical agents. Further advancement of transdermal drug delivery requires the development of novel delivery systems that are suitable for modern, macromolecular protein and nucleotide therapeutic agents. Significant effort has already been devoted to obtain a functional understanding of the physical barrier properties imparted by the epidermis, specifically the membrane structures of the stratum corneum. However, structural observations of membrane systems are often hindered by low resolutions, making it difficult to resolve the molecular mechanisms related to interactions between lipids found within the stratum corneum. Several models describing the molecular diffusion of drug molecules through the stratum corneum have now been postulated, where chemical permeation enhancers are thought to disrupt the underlying lipid structure, resulting in enhanced permeability. Recent investigations using biphasic vesicles also suggested a possibility for novel mechanisms involving the formation of complex polymorphic lipid phases. In this review, we discuss the advantages and limitations of permeation‐enhancing strategies and how computational simulations, at the atomic scale, coupled with physical observations can provide insight into the mechanisms of diffusion through the stratum corneum. WIREs Nanomed Nanobiotechnol 2011 3 449–462 DOI: 10.1002/wnan.147

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Figure 1.

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

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Figure 2.

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).

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Figure 3.

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.

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Figure 4.

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.

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Figure 5.

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.

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Figure 6.

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.

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James F. Leary

James F. Leary
has been contributing to nanomedical research and technologies throughout his career. Such contributions include the invention of high-speed flow cytometry, cell sorting techniques, and rare-event methods. Dr. Leary’s current research spans across three general areas in nanomedicine. The first is the development of high-throughput single-cell flow cytometry and cell sorting technologies. The second explores BioMEMS technologies. These include miniaturized cell sorters, portable devices for detection of microbial pathogens in food and water, and artificial human “organ-on-a-chip” technologies which consists of developing cell culture chips capable of simulating the activities and mechanics of entire organs and organ systems. His third area of research aims at developing smart nano-engineered systems for single-cell drug or gene delivery for nanomedicine. Dr. Leary currently holds nine issued U.S. Patents with four currently pending, and he has received NIH funding for over 25 years.

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