Peptides as functional excipients for drug delivery

Abstract

Peptides have a wide variety of amino acid compositions, sequences and conformations, which allow high specificity and great functionality. Biodegradable peptides arouse less concern about toxicity and tissue accumulation, while short peptides contribute to easy design and manufacturing, high quality, and low production costs. Thanks to these advantages, peptides can be used as high-functional excipients for drug delivery systems (DDS). Recent research has demonstrated the high performance of peptide excipients, including easy drug loading and sustained release of various drugs by self-assembling peptides, efficient cellular uptake/endosomal escape and higher transmucosal permeation by cell-penetrating peptides, and effective nanoparticle DDS for targeting cells and tissues using peptide ligands. Research progress has led to the approval of some new peptide excipients for clinical use, such as PuraStat and RTP004. In addition, green synthesis of peptides at low cost is also important for the use of peptides as excipients, and recent research will enable environmentally friendly solvents and purification. Further, given the importance of regulation to ensure the safety and quality of the new peptide excipients for broad use in many drug products, this review also summarizes current regulatory information on peptides and excipients.

Introduction

Peptides and proteins are composed of 20 amino acids, and their interaction is the most important for biological function in the body. Various proteins such as collagen, keratin and actin cytoskeleton play major roles as scaffolding for living organisms . Almost all reactions in the body are catalyzed by protein enzymes. Biological recognition and communication are mediated by protein antibodies and receptors, and moreover by peptide hormones including insulin, vasopressin, oxytocin and gastrin. Compared with small molecules, the large size of proteins and peptides provides a much wider diversity of amino acid compositions and sequences, and various conformations, which enable more specific interactions and a huge range of functions. Peptides have high selectivity and specificity towards cell surface receptors, and more than 80 peptide therapeutic drugs have been approved for a variety of diseases, including diabetes, cancer, osteoporosis, multiple sclerosis, HIV infection, and chronic pain.

Since the first medical use of insulin almost a century ago, many peptide drugs have been developed [9]. Most peptide drugs have low oral bioavailability and parenteral formulations are required. Peptides are often unstable in aqueous solution, and while lyophilized formulations are one option, liquid formulations have some advantages in time-consumption and cost. To protect the peptide against hydrolysis in the formulations, the best excipients are selected from buffers, polyols, antioxidants, surfactants, chelating agents and co-solvents, and the pH, manufacturing process and packaging are optimized. Moreover, peptide drugs have short half-lives in blood, and sustained release drug delivery systems (DDS) are useful in reducing dosing frequency. Several products have been marketed using biodegradable poly(lactic-co-glycolic acid) or poly(lactic acid) such as Lupron Depot® [9]. DDS have also contributed to a change in dosing route of peptide drugs, including inhalable insulin Exubera®, nasal desmopressin DDAVP®, and oral semaglutide Rybelsus®.

From a safety perspective, peptides and proteins are usually metabolized to amino acids, which results in few toxic incidents. The short half-life of peptides in blood also contributes to lessening their accumulation in tissues and greater safety. Therapeutic proteins and antibodies can trigger immune responses, whereas peptides are potentially less immunogenic owing to their small size. Peptides are composed of less than 40 amino acids, making them much shorter than proteins and antibodies, and giving them advantages in their design, manufacturability and quality. Peptides can be chemically synthesized, which allows rapid cost-effective optimization of compositions and sequences [8], well-controlled purity, and relatively lower manufacturing costs than recombinant proteins and antibodie. Proteins and antibodies undergo degradation and unintended aggregation in storage; in contrast, peptides are more stable and easier to store.

Importantly, the delivery of active drug substances to patients as drug products requires the use of pharmaceutical excipients (inactive additives). To ensure stable high performance (high efficacy, low side effects and user-friendly dosing) of products in the market and in clinical trials, several excipients are usually selected. These are included in dosage forms to ensure stabilization, solubilization, sustained release, absorption enhancement, control of in vivo drug distribution, and easy dosing, among other reason. Polymer excipients are also frequently used in all drug products, such as oral tablets and injections; these include polysaccharides, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, and polyacrylate or polymethacrylate esters. These polymers consist of 1–3 monomer blocks; in contrast, peptides are composed of 20 different amino acids. Since the larger variety of compositions and sequences enables higher functionality, peptides are potentially able to act as powerful pharmaceutical excipients for DDS, and several uses have been investigated for sustained release, penetration enhancement and targeting to particular kinds of cells. This article summarizes recent studies on peptide excipients for DDS, including self-assembling peptides (SAP), cell-penetrating peptides (CPP) and peptide ligands on nanoparticles.

To use peptides as excipients, stable manufacturing is important in achieving a stable market supply of drug products to patients without creating shortages. Current peptide synthesis is wasteful and not environmentally friendly. This is particularly true for solvents used in synthesis and purification. Greener and more efficient synthesis of peptides with a smaller negative environmental impact and lower cost will increase the use of the peptide excipients. This review summarizes research on environmentally friendly peptide synthesis, especially regarding the replacement of solvents. Moreover, the safety and quality of new peptide excipients are essential for patients, and extensive safety assessment and proper quality control are therefore required for their approval [25,26]. To promote new applications of peptide excipients, it is preferable to clarify what types and level of studies are required for their approval. This article reviews related guidance published by health authorities; nonclinical/clinical toxicity assessment for new excipients and peptides; and tests for quality, especially for the purity of peptides. A deeper understanding of progress in DDS research, green chemistry and regulation will work together to aid the delivery of many drug products containing peptide excipients with high performance for more patients.