Therapeutics
tively low bioavailabilities of ≤10%. As such, high- er doses are required to obtain the same therapeu- tic effect in an oral formulation. For example, we are currently conducting a Phase IIa trial of its oral tablet leuprolide comparing once- and twice-per- day doses of a 4mg oral tablet with a single, monthly depot injection of LUPRON DEPOT 3.75mg.
to or exceeding the standard of care) ultimately hinges on whether the peptide is absorbed through the intestine and enters the bloodstream as an intact chemical species. As referenced previously, peptides have relatively large molecular weights and hydrophilicity, resulting in poor penetration across the intestinal epithelium. This may be the most chal- lenging barrier to oral peptide delivery. As peptides reach the intestinal epithelium, they first encounter an exogenous mucus gel layer con- taining proteases and antibodies, which together reduce the rate of diffusion to the epithelial sur- face. Attempts to overcome mucoadhesion have focused on incorporation of mucolytics or use of hydrophilic PEGylated nanoparticles, which avoid entrapment in mucus glycoprotein meshes. An alternative approach is to exploit mucoadhesion to increase the residence time of the dosage form in the small intestine. However, greater success has been achieved via the use of permeability enhancers, such as lauroyl carnitine chloride (LCC), palmitoyl carnitine chlo- ride (PCC) and sodium taurodeoxycholate, which facilitate peptide entry into the bloodstream. Such permeability enhancers function by enabling the transport of peptide molecules through the epithe- lium via passive movement across the epithelial tight junctions. Finally, after overcoming these obstacles, the successful development of an oral peptide must accept that the bioavailability of an orally-deliv- ered peptide will be less than that of a comparable dose of a parenterally-delivered peptide. Even the best oral peptide formats are known to have rela-
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Given such differentials, developers must care- fully consider the practicality of transitioning a peptide to an oral form based on the cost per goods. Simply put, the cost of the additional API (and production) must be less than the expected market expansion for an oral formulation. If not, then the Holy Grail is but an empty chalice. While this may seem discouraging on the sur- face, there has been significant investment in the development of oral peptide dosage forms by spe- cialised drug delivery companies. This is based on the clear advantages that such medications offer patients, prescribers and pharmaceutical develop- ers, alike. Oral leuprolide demonstrates this poten- tial. Not only could an oral leuprolide tablet help to potentially convert current injectable leuprolide to oral, but the oral formulation could drive the use of leuprolide earlier and more often, including use prior to hormonal contraceptives, use pre- and post-surgical procedures and use in women cur- rently untreated. As well, it could enable the expansion of GnRH agonist therapy to indications where an injectable is undesirable, such as the treatment of uterine fibroids. Ultimately, not all peptide therapeutics are appropriate for oral administration due to various constraints, from physiochemical to economic. However, for those that meet the necessary criteria, advances in formulation technologies coupled with favourable market dynamics will continue to drive interest across the entire prescription drug spec- trum for safe and effective orally-administered peptide therapeutics.
DDW
Dr Paul Shields is the Chief Operating Officer of Enteris BioPharma, a privately-held, New Jersey- based biotechnology company offering innovative formulation solutions built around its proprietary drug delivery technologies. Dr Shields holds a PhD in biochemistry from the University of Pennsylvania and a BS in chemical engineering from the University of Michigan and has more than 24 years of experience in the biopharmaceutical industry, focusing on Chemistry, Manufacturing and Controls (CMC) for a variety of products.
Drug Discovery World Fall 2017
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