Designing Formulation Strategies for Enhanced Stability of Therapeutic Peptides in Aqueous Solutions: A Review

Abstract

Over the past few decades, there has been a tremendous increase in the utilization of therapeutic peptides. Therapeutic peptides are usually administered via the parenteral route, requiring an aqueous formulation. Unfortunately, peptides are often unstable in aqueous solutions, affecting stability and bioactivity. Although a stable and dry formulation for reconstitution might be designed, from a pharmaco-economic and practical convenience point of view, a peptide formulation in an aqueous liquid form is preferred. Designing formulation strategies that optimize peptide stability may improve bioavailability and increase therapeutic efficacy. This literature review provides an overview of various degradation pathways and formulation strategies to stabilize therapeutic peptides in aqueous solutions. First, we introduce the major peptide stability issues in liquid formulations and the degradation mechanisms. Then, we present a variety of known strategies to inhibit or slow down peptide degradation. Overall, the most practical approaches to peptide stabilization are pH optimization and selecting the appropriate type of buffer. Other practical strategies to reduce peptide degradation rates in solution are the application of co-solvency, air exclusion, viscosity enhancement, PEGylation, and using polyol excipients.

Atomistic molecular insight on Angiotensin-(1-7) interpeptide interactions

“…Mimicking the behavior observed at neutral pH but with low salt concentration, all peptides in the simulated system belong to the organic-rich phase, meanwhile, the waterrich phase of such a solution is composed of pure water. In summary, our results make sense qualitatively with the pH-dependant experimental instability reported for Ang- (1)(2)(3)(4)(5)(6)(7) in aqueous solutions: we can show here that even in the case where there is instability (acidic pH), peptides tend to interact but in less degree, forming smaller clusters compared to that in which they form part of the organic-rich phase (neutral pH). Additionally, these results open the possibility to modulate Ang-(1-7) aggregation through salt concentration in cases where Ang-(1-7) stability is required like in the case of cardioprotective solutions.…”

“…3,4 However, therapeutic peptides pose considerable challenges in their aqueous formulation or their delivery in an aqueous environment, particularly concerning their physical stability. 5,6 Physical instability implies changes to the higher-order structures, usually involving noncovalent bonds: early oligomerization, aggregation, and further precipitation. 5 Since peptide association to form either amorphous aggregates or highly structured fibrillar species, could limit their clinical or pharmaceutical applications, or be associated with diseases, 7 it is crucial to study the factors affecting it.…”

“…Angiotensin-(1-7) (Ang- (1)(2)(3)(4)(5)(6)(7)) is an endogenous bio-active therapeutic heptapeptide involved in many clinical conditions ranging from cancer, cardiovascular diseases, pulmonary diseases, diabetes and COVID-19, 8,9 which guarantees its physiological and therapeutically relevance. Ang-(1-7) shows a β-sheet structure in solution, with a bend stabilized by interactions between residues Val3 and Tyr4 according to circular dichroism and NMR data.…”

Atomistic Molecular Insights into Angiotensin-(1-7) Interpeptide Interactions

“…Nowadays, there has been a dramatic expansion in the discovery/design of bioactive peptides and the interest in their potential use in therapeutics . Moreover, this number is likely to continue to increase in the coming years. , However, therapeutic peptides pose significant challenges in their aqueous formulation or their delivery in an aqueous environment, particularly with respect to their physical stability. , Physical instability implies changes in the higher order structures, usually involving non-covalent bonds: early oligomerization, aggregation, and further precipitation . Since the association of peptides to form either amorphous aggregates or highly structured fibrillar species could limit their clinical or pharmaceutical applications or be associated with diseases, it is crucial to study the factors that influence it.…”

“…3,4 However, therapeutic peptides pose significant challenges in their aqueous formulation or their delivery in an aqueous environment, particularly with respect to their physical stability. 5,6 Physical instability implies changes in the higher order structures, usually involving non-covalent bonds: early oligomerization, aggregation, and further precipitation. 5 Since the association of peptides to form either amorphous aggregates or highly structured fibrillar species could limit their clinical or pharmaceutical applications or be associated with diseases, 7 it is crucial to study the factors that influence it.…”