DISCOVERY OF TRANSDERMAL PENETRATION ENHANCERS BY HIGH-THROUGHPUT SCREENING.

• TR Number: 319
• Keywords: Anionic surfactants, Azone compounds, Azone-like compounds, Cationic surfactants, Chemical penetration enhancers (CPEs), Conductivity enhancement ratios, Cytokines, Drug delivery, Drug transport, ELISA, Enzyme-linked immunosorbent assay (ELISA), EpiDerm, Fatty acids, Fatty esters, Franz diffusion cells (FDC), High-throughput screening, IL-1a, INSIGHT, In vitro skin impedance guided high-throughput (INSIGHT) screening, Interleukin 1a, Interleukin 1a assay, Irritation, MTT, MTT ET-50 tissue viability assay, MTT assay, Macromolecular drugs, Nonionic surfactants, Penetration enhancers, Permeation enhancement, SCOPE, Safety studies, Skin conductance, Skin permeability, Stratum corneum (SC), Surfactants, Synergistic combinations of penetration enhancers (SCOPE), Synergy value, Systemic drug administration, Transdermal, Transdermal delivery, Transdermal drug delivery, Transdermal patch, Triton X-100, Zwitterionic, Zwitterionic surfactants

Although transdermal drug delivery is more attractive than injection, it has not been applied to macromolecules because of low skin permeability. Here scientists at UC Santa Barbara describe particular mixtures of penetration enhancers that increase skin permeability to macromolecules (~1-10 kDa) by up to ~100-fold without inducing skin irritation. The discovery of these mixtures was enabled by an experimental tool, in vitro skin impedance guided high-throughput (INSIGHT) screening, which is >100-fold more efficient than current tools. In vitro experiments demonstrated that the mixtures delivered macromolecular drugs, includinging heparin, leutinizing hormone releasing hormone (LHRH) and oligonulceotides, across the skin. In vivo experiments on hairless rats with leuprolide acetate confirmed the potency and safety of one such mixture, sodium laureth sulfate (SLA) and phenyl piperazine (PP). These studies show the feasibility of using penetration enhancers for systemic delivery of macromolecules from a transdermal patch. NOTE: EpiDerm tissues were used to assess the skin irritation potential of the leading permeation enhancer candidates as determined by INSIGHT analysis. EpiDerm has recently emerged as an excellent method for assessing irritation potential.