Therapeutics


oral leuprolide tablet could offer a more patient- friendly alternative to monthly depot injections, potentially encouraging physicians and patients to utilise the medication earlier and more often. Market estimates suggest such a drug could pro- duce revenues in excess of $600 million annually in the US.


In developing its oral leuprolide tablet, biotech- nology company Enteris BioPharma utilised a tech- nology platform designed to provide protection against the harshness of the digestive system and then promote absorption of the leuprolide into the bloodstream. First, to overcome the stomach’s highly acidic environment, the oral tablet was encapsulated in an enteric coating. Simple in con- cept, an enteric coating is a polymer barrier applied to an oral medication that prevents its dissolution in the gastric environment.


Enteric coatings work by presenting a surface that is stable at the highly acidic pH found in the stomach, yet dissolves at the higher pH of the small intestine and at locations within the intestinal tract to enable optimal drug absorption. A variety of materials can be utilised as an enteric coating, pro- vided the material shields the peptide drug in the stomach and enables its release in the intestine where absorption into the bloodstream can occur. Protecting against the acidic gastric environment


Drug Discovery World Fall 2017


and enabling dissolution in the small intestine is but the first hurdle that must be addressed. The next, limiting proteolytic degradation in the jejunum, is a considerably more difficult (and crit- ical) proposition as many peptides are highly vul- nerable in the soluble form to peptidases in the lumen prior to reaching the systemic circulation. Though it is difficult to completely inhibit the actions of luminal proteases, scientists utilised pro- tease inhibitors to create a protective microenvi- ronment for its oral leuprolide tablet. Without such protective measures, the protease enzymes would immediately act upon the leuprolide, break- ing it down for ingestion into the bloodstream; no different than protein consumed as food. Despite the clear need for protease inhibitors in the oral delivery of a peptide, caution must be heeded when selecting a protease inhibitor, as many are not considered safe for use as excipients and inhibition of such a ubiquitous biological func- tion can be risky. Developers, therefore, are encouraged to utilise technologies that limit the effects of such inhibitors to the GI lumen locally, and transiently, to avoid systemic toxicity. Though shielding against the digestive system is paramount to administering a peptide orally, success in developing an efficacious oral peptide (one that elicits the desired therapeutic response comparable


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