Ammonium glycyrrhizate skin delivery from ultradeformable liposomes: A novel use as an anti-inflammatory agent in topical drug delivery

Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a “screening hit” through a “drug lead” to a “marketed drug” is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis. While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future.

This work describes a novel carrier for enhanced skin delivery, the ethosomal system, which is composed of phospholipid, ethanol and water. Ethosomal systems were much more efficient at delivering a fluorescent probe to the skin in terms of quantity and depth, than either liposomes or hydroalcoholic solution. The ethosomal system dramatically enhanced the skin permeation of minoxidil in vitro compared with either ethanolic or hydroethanolic solution or phospholipid ethanolic micellar solution of minoxidil. In addition, the transdermal delivery of testosterone from an ethosomal patch was greater both in vitro and in vivo than from commercially available patches. Skin permeation of ethosomal components, ethanol and phospholipid, was demonstrated in diffusion-cell experiments. Ethosomal systems composed of soy phosphatidylcholine 2%, ethanol 30% and water were shown by electron microscopy to contain multilamellar vesicles. 31P-NMR studies confirmed the bilayer configuration of the lipids. Calorimetry and fluorescence measurements suggested that the vesicular bilayers are flexible, having a relatively low T(m) and fluorescence anisotropy compared with liposomes obtained in the absence of ethanol. Dynamic light scattering measurements indicated that ethanol imparted a negative charge to the vesicles. The average vesicle size, as measured by dynamic light scattering, was modulated by altering the ethosome composition. Experiments using fluorescent probes and ultracentrifugation showed that the ethosomes had a high entrapment capacity for molecules of various lyophilicities.

The skin is refractive to most molecules, especially hydrophilic ones, despite the existence of trans-barrier pathways. It is essential to maintain this protective barrier even after breaching skin surface for purposes of transdermal drug delivery to cope with cutaneous microbiota. Mechanical abraders or local energy dischargers (porators) or else hard, sharp objects (perforators, micro-needles) can punch a limited number (approximately 10(2)cm(-2)) of relatively wide (> or =10(3)nm) openings in the skin barrier, which then lets transiently (approximately 1 day) small drug quantities ( or =10(3)nm) ballistic droplets or particles also insert small drug amounts (approximately 1mg) into the upper skin through the > or =10(6)cm(2) pores they create. The latter "skin breaching" method is approved for use in humans, whereas the hard nano-sized (5 nm-10 microm) skin perforators are still in development for transdermal drug delivery. Alternatively, controlled and reliable drug delivery across skin barrier can be achieved with sufficiently deformable and stable nano-sized carriers. Such "soft" skin penetrators are typically composite colloids. As such they must obtain, or retain, their ability to act as drug carriers on, in, and ideally below skin barrier(s). If properly designed and applied, such self-regulating, ultra-adaptable, and stable hetero-aggregates can open spontaneously and carry drugs through < or =10(9)cm(-2) cutaneous pores in the primary skin barrier and minimise cutaneous drug clearance; this permits deep/targeted deposition and prolonged action of the carrier-transported drugs. Therapeutic products based on ultra-adaptable, self-regulating, nano-sized (approximately 10(2)nm) carriers are under development. The first one is already approved in Switzerland. Copyright 2009. Published by Elsevier B.V.