Novel Penetration Enhancers A Amino Acid

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Most of classical penetration enhancers improve the paracellular transport across a biological membrane by damaging the tight junctions to varying degrees by their nonspecific actions. As a result, few of them are approved by the FDA because of safety concern. Emisphere Technologies synthesized a series of small molecular weight a-amino acids, which are used to promote oral delivery (Fig. 6) (40,41). These delivery agents successfully increased absorption of several macromolecules in vivo in rats and primates, including humans, such as salmon calcitonin (42), interferon-a (43), heparin (44), and human growth hormone (hgH) (45). Wu (41) showed that these carriers can increase the permeability coefficient of human growth hormone across Caco-2 monolayers by 10-fold. Although it did have some effects on para-cellular transport, the major pathway was observed to be transcellular. Failure of these carriers to improve the transport of hydrocortisone, a transcellular marker, in Caco-2 monolayers showed that these carriers have a specific interaction with hGH, which makes the hGH more transportable, and such an interaction does not exist in the case of hydrocortisone. It was clearly established that these carriers do not damage cell membranes and thus are not classical penetration enhancers. Moreover, the carrier-drug complex is not absorbed by an active transport process.

Figure 6 Chemical structures of various amino acid derivative carriers. (From Ref.

The working mechanistic assumption is that the carrier shields those hydro-philic groups on the molecule that restrain absorption.

Previous work in our laboratory showed that these carriers increase the permeability coefficient of hGH across the cornea of a rabbit by 10-fold (46). Further study is ongoing in our laboratory to confirm the efficacy and toxicity of these carriers as delivery agents/carriers for ocular drug delivery.

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