Physicochemical and Formulation Developability Assessment for Therapeutic Peptide Delivery—A Primer

Transdermal drug delivery has made an important contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. First-generation transdermal delivery systems have continued their steady increase in clinical use for delivery of small, lipophilic, low-dose drugs. Second-generation delivery systems using chemical enhancers, noncavitational ultrasound and iontophoresis have also resulted in clinical products; the ability of iontophoresis to control delivery rates in real time provides added functionality. Third-generation delivery systems target their effects to skin's barrier layer of stratum corneum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound. Microneedles and thermal ablation are currently progressing through clinical trials for delivery of macromolecules and vaccines, such as insulin, parathyroid hormone and influenza vaccine. Using these novel second- and third-generation enhancement strategies, transdermal delivery is poised to significantly increase its impact on medicine.

The suite of currently used drugs can be divided into two categories - traditional 'small molecule' drugs with typical molecular weights of 5000 Da that are not orally bioavailable and need to be delivered via injection. Due to their small size, conventional small molecule drugs may suffer from reduced target selectivity that often ultimately manifests in human side-effects, whereas protein therapeutics tend to be exquisitely specific for their targets due to many more interactions with them, but this comes at a cost of low bioavailability, poor membrane permeability, and metabolic instability. The time has now come to reinvestigate new drug leads that fit between these two molecular weight extremes, with the goal of combining advantages of small molecules (cost, conformational restriction, membrane permeability, metabolic stability, oral bioavailability) with those of proteins (natural components, target specificity, high potency). This article uses selected examples of peptides to highlight the importance of peptide drugs, some potential new opportunities for their exploitation, and some difficult challenges ahead in this field. © 2012 John Wiley & Sons A/S.

The notable expansion of peptide therapeutics development in the late 1990s and the 2000s led to an unprecedented number of marketing approvals in 2012 and has provided a robust pipeline that should deliver numerous approvals during the remainder of the 2010s. To document the current status of the pipeline, we collected data for peptide therapeutics in clinical studies and regulatory review, as well as those recently approved. In this Foundation review, we provide an overview of the pipeline, including therapeutic area and molecular targets, with a focus on glucagon-like peptide 1 receptor agonists. Areas for potential expansion, for example constrained peptides and peptide-drug conjugates, are profiled. Copyright © 2013 Elsevier Ltd. All rights reserved.