Abstract
Transdermal drug delivery has made a notable contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. While transdermal delivery systems would appear to provide an attractive solution for local and systemic drug delivery, only a limited number of drugs can be delivered through the outer layer of the skin. The most difficult to deliver in this way are hydrophilic drugs. The aquatic phylum Cnidaria, which includes sea anemones, corals, jellyfish and hydra, is one of the most ancient multicellular phyla that possess stinging cells containing organelles (cnidocysts), comprising a sophisticated injection system. The apparatus is folded within collagenous microcapsules and upon activation injects a thin tubule that immediately penetrates the prey and delivers its contents. Here we show that this natural microscopic injection system can be adapted for systemic transdermal drug delivery once it is isolated from the cells and uploaded with the drug. Using a topically applied gel containing isolated natural sea anemone injectors and the muscarinic receptor antagonist scopolamine, we found that the formulated injectors could penetrate porcine skin and immediately deliver this hydrophilic drug. An in-vivo study in pigs demonstrated, for the first time, rapid systemic delivery of scopolamine, with Tmax of 30 minutes and Cmax 5 times higher than in controls treated topically with a scopolamine-containing gel without cnidocysts. The ability of the formulated natural injection system to penetrate a barrier as thick as the skin and systemically deliver an exogenous compound presents an intriguing and attractive alternative for hydrophilic transdermal drug delivery.
Highlights
Transdermal delivery has advantages over conventional drug delivery systems in that it reduces first-pass metabolism, eliminates drastic drug fluctuations, prevents adverse side effects, and increases patient compliance
We have previously shown that the sea anemone micro-injection system can be applied for topical delivery, is compatible with hydrophilic compounds, and is clinically safe [16,17,18]
Preparation of Cnidocysts for Drug Delivery We used the naturally secreted acontial filaments of the sea anemone Aiptasia diaphana, which are highly enriched with cnidocysts (Fig. 2a)
Summary
Transdermal delivery has advantages over conventional drug delivery systems in that it reduces first-pass metabolism, eliminates drastic drug fluctuations, prevents adverse side effects, and increases patient compliance. The passive approach includes the use of different types of topical formulations, including chemical enhancers, liposomes, ethosomes, or large reservoir-type patches [4,5] While these technologies have the advantage of high patient compliance, they usually require a prolonged application time and are limited to molecules that are both lipophilic and small. The physical approach primarily employs high-energy devices such as needle-free injectors, low-frequency ultrasound, iontophoresis, electroporation, microneedles, or thermal procedures [6,7]. These advanced methods have the advantage of rapidly permeating the skin barrier, but they generally entail sophisticated devices, professional administration, higher costs, and lower patient compliance. Owing to these limitations relatively few drugs can currently be introduced transdermally, with particular difficulty experienced in the delivery of hydrophilic drugs through this route [8]
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