Drug delivery across the skin.
Since the introduction of the first through the skin (TTS) therapeutic in 1980, a total of 34 TTS products have been marketed and numerous drugs have been tested by more than 50 commercial organisations for their suitability for TTS delivery. Most of the agents which have been tested have had low molecular weights, due to the impermeability of the skin barrier. This barrier resides in the outermost skin layer, the stratum corneum. It is mechanical, anatomical, as well as chemical in nature; laterally overlapping cell multi-layers are sealed by tightly packed, intercellular, lipid multi-lamellae. Chemical skin permeation enhancers increase the transport across the barrier by partly solubilising or extracting the skin lipids and by creating hydrophobic pores. This is often irritating and not always well-tolerated. The TTS approach allows drugs (< 400 kDa in size) to permeate through the resulting pores in the skin, with a short lag-time and subsequent steady-state period. Drug bioavailability for TTS delivery is typically below 50%, avoiding the first pass effect. Wider, hydrophilic channels can be generated by skin poration, with the aid of a small electrical current (> 0.4 mA/cm2) across the skin (iontophoresis) or therapeutic ultrasound (few W/cm2; sonoporation). High-voltage (> 150 V, electroporation) widens the pores even more and often irreversibly. These standard poration methods require experience and equipment and are therefore, not practical; at best, charged/small molecules (< or = 4000 kDa in size) can be delivered efficiently across the skin. In spite of the potential harm of gadget-driven skin poration, this method is used to deliver molecules which conventional TTS patches are unable to deliver, especially polypeptides. Lipid-based drug carriers (liposomes, niosomes, nanoparticle microemulsions, etc.) were proposed as alternative, low-risk delivery vehicles. Such suspensions provide an improved drug reservoir on the skin, but the aggregates remain confined to the surface. Conventional carrier suspensions increase skin hydration and/or behave as skin permeation enhancers. The recently developed carriers; Transferomes, comprise pharmaceutically-acceptable, established compounds and are thought to penetrate the skin barrier along the naturally occurring transcutaneous moisture gradient. Transfersomes are believed to penetrate the hydrophilic (virtual) channels in the skin and widen the former after non-occlusive administration. Both small and large hydrophobic and hydrophilic molecules are deliverable across the stratum after conjugation with Transfersomes. Drug distribution after transdermal delivery probably proceeds via the lymph. This results in quasi-zero order kinetics with significant systemic drug levels reached after a lag-time of up to a few hours. The relative efficiency of TTS drug delivery with Transfersomes is typically above 50 %; with the added possibility of regional drug targeting.
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Medizinische Biophysik, Klinikum r.d.I., Technische Universität München, Ismaninger Str. 22, D-81675 München, Germany.