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

Abstract

Abstract. Peptides are an important class of endogenous ligands that regulate key biological cascades. As such, peptides represent a promising therapeutic class with the potential to alleviate many severe disease states. Despite their therapeutic potential, peptides frequently pose drug delivery challenges to scientists. This review introduces the physicochemical, biophysical, biopharmaceutical, and formulation developability aspects of peptides pertinent to the drug discovery-to-development interface. It introduces the relevance of these properties with respect to the delivery modalities available for peptide pharmaceuticals, with the parenteral route being the most prevalent route of administration. This review also presents characterization strategies for oral delivery of peptides with the aim of illuminating developability issues with the drug candidate. A brief overview of other routes of administration, including inhaled, transdermal, and intranasal routes, is provided as these routes are generally preferred by patients over injectables. Finally, this review presents formulation techniques to mitigate some of the developability obstacles associated with peptide delivery. The authors emphasize opportunities for the thoughtful application of pharmaceutical science to the development of peptide drugs and to the general advancement of this promising class of pharmaceuticals.

Mechanisms Influencing the Pharmacokinetics and Disposition of Monoclonal Antibodies and Peptides

“…The genesis of the transformation and modification processes can be a myriad of possibilities during expression, purification, storage, and/or in vivo exposure. This section will cover a high-level overview of these mechanisms in the absence of the consideration of their origin; however, a substantial discussion on these processes has been reviewed extensively elsewhere and the reader is directed to other reviews for more information (Bak et al, 2015;Lapto s and Omersel, 2018). Additionally, it has been speculated by our laboratory and others that transformations or modifications can influence the clearance of biologics, particularly through scavenger receptors (Ashraf and Sahu, 2012;Zani et al, 2015;Datta-Mannan et al, 2016;PrabhuDas et al, 2017).…”

“…Along with glycosylation-based modifications, there are noteworthy concerns around the transformation of mAbs and peptides, which may result in perturbations to structure and function that influence PK and disposition. The transformation of mAbs and peptides via deamidation, oxidation, and isomerization of certain residues is commonly assessed during chemical stability testing in vitro as part of formulation development at relatively high protein concentrations (Bak et al, 2015;Lapto s and Omersel, 2018). Due to bioanalytical challenges around detection in the complex environmental milieu of biologic samples, progress in the characterization of transformation in vivo has been slow; however, there are a handful of studies examining the occurrence of these processes in vivo and the importance of their characterization on the clearance and disposition of mAbs and peptides.…”

Penetration of the blood-brain barrier by peripheral neuropeptides: new approaches to enhancing transport and endogenous expression

“…Peptide drugs are commonly administered intravenously due to poor oral bioavailability, such as enzymatic degradation and limited absorption by the gastrointestinal system (Bak, et al, 2015, Bruno, et al, 2013). Various surface modification processes have been explored to improve the peptide bioavailability (i.e.…”

“…structural modification for better stability or antibody tagging for better targeting). The peptide also can be stabilized by including enzyme inhibitors in the formulation to prevent degradation in the gastrointestinal tract (Bak, et al, 2015, Dufès, 2011). In addition, the short half-life of peptides limits their utility as therapeutic agents so peptide fusion with albumin, PEGylation or acetylation strategies have been developed to increase peptide half-life (Dwibhashyam and Nagappa, 2008).…”

Initial Risk Assessment as part of the Quality by Design in peptide drug containing formulation development

“…Oral peptide drug delivery has several challenges and many risks because peptide drugs are more complex and heterogeneous in nature than chemical drugs [28][29] [30]. Every product is unique with several risks related [31]. Also, the European Medicine Agency (EMA) says that: "Biological products possess such a large number of quality attributes that it might not be possible to fully evaluate the impact on safety and efficacy of each one.…”