Transdermal Delivery of Scopolamine by Natural Submicron Injectors: In-Vivo Study in Pig

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

Calculated pharmacokinetic parameters of scopolamine in pig plasma after a 5-minute topical application of the drug.

*<p>Cmax, peak plasma concentration; Tmax, time to maximal concentration; t_½, half-life elimination time; AUC, Area under the plasma concentration time curve.</p

Preparation of cnidocysts.

<p>(a) A filament of <i>Aiptasia diaphana</i> containing packed cnidocysts. Bar, 100 µm. (b) Isolated cnidocysts. Bar, 25 µm. (c), A discharging cnidocyst. Following release of the folded 150-µm injector, only its smooth tip (50 µm long, submicron diameter) can penetrate the skin (see arrow). Bar, 25 µm.</p

Plasma levels of scopolamine in pigs after short topical exposure.

<p>Test and control groups were exposed for 5 minutes to the same solution of 5% scopolamine HBr. Averaged values (means ± s.d) of the test group (▪) treated with gel formulation containing isolated cnidocysts and of the control group (Δ) treated with gel formulation only.</p

Scopolamine 5-minute <i>in-vitro</i> study.

<p>Cumulative permeation of scopolamine delivered by cnidocyst gel (<i>n</i> = 11) compared to control gel without microcapsules (<i>n</i> = 5) after 24 hours. Error bars represent s.d.</p

Mode of action of the cnidocyst system.

<p>The intact dry cnidocyst (a) is activated by the hydrophilic drug solution (b) water molecules (blue triangle) and the soluble drug (green circles) penetrate the porous wal<b>l</b> of the cnidocyst, resulting in discharge of the tubule and injection of its microcapsule content through the tubule to the skin (c).</p