An Update on Pharmaceutical Strategies for Oral Delivery of Therapeutic Peptides and Proteins in Adults and Pediatrics

Abstract

While each route of therapeutic drug delivery has its own advantages and limitations, oral delivery is often favored because it offers convenient painless administration, sustained delivery, prolonged shelf life, and often lower manufacturing cost. Its limitations include mucus and epithelial cell barriers in the gastrointestinal (GI) tract that can block access of larger molecules including Therapeutic protein or peptide-based drugs (TPPs), resulting in reduced bioavailability. This review describes these barriers and discusses different strategies used to modify TPPs to enhance their oral bioavailability and/or to increase their absorption. Some seek to stabilize the TTPs to prevent their degradation by proteolytic enzymes in the GI tract by administering them together with protease inhibitors, while others modify TPPs with mucoadhesive polymers like polyethylene glycol (PEG) to allow them to interact with the mucus layer, thereby delaying their clearance. The further barrier provided by the epithelial cell membrane can be overcome by the addition of a cell-penetrating peptide (CPP) and the use of a carrier molecule such as a liposome, microsphere, or nanosphere to transport the TPP-CPP chimera. Enteric coatings have also been used to help TPPs reach the small intestine. Key efficacious TPP formulations that have been approved for clinical use will be discussed.

Phage-Displayed Peptides for Targeting Tyrosine Kinase Membrane Receptors in Cancer Therapy

“…The use of peptides as potential drugs may provide several benefits. Compared to other pharmaceutical molecules, peptides have fewer side effects [61]. They are smaller than antibodies and can be easily synthesized and modified to improve stability, solubility, tissue penetration, and biocompatibility [62,63].…”

Current Status and Perspectives of Oral Therapeutic Protein and Peptide Formulations: A Review

“…Thus, the formulation should ensure to protect the protein through minute changes that occur during the processing of oral drugs [25]. Any changes in these conditions result in physical instabilities resulting in the making or breaking of the interactions between different amino acids to maintain structural integrity causing a denaturation [22]. Furthermore, proteins demonstrate aqueous solubility depending of various factors such as pH, temperature, isoelectric point, presence of metallic ions and hydrophobicity that are measured using modern analytical methods such as X-ray diffraction, dynamic light scattering, size exclusion chromatography, mass spectroscopy (MS), circular dichroism spectroscopy, nuclear magnetic resonance spectroscopy, and Fourier transform infrared (FTIR) spectroscopy [26].…”

“…One of the key factors responsible for an optimal activity of the therapeutic agents is the route of delivery. Although the most commonly employed administration is through subcutaneous, intramuscular and intravenous systems, oral drugs are the most widely accepted as they are less painful during administration [19,20,22]. Advancement in technology has led to the association of certain microparticles with proteins in order to be delivered through intramuscular or subcutaneous modes.…”

“…Despite its wide acceptance, their development is complicated because of their high molecular weight, low stability under physiological conditions, low permeability to the intracellular targets and shorter half-life [17,21]. On these lines, an ideal oral therapeutic protein should have efficacy along with protective ability against varying pH and proteolytic damage, and ensure optimal absorption from the intestine to release its action through the blood stream [22]. The stability and functionality of the therapeutic proteins can be improved by performing certain chemical modifications with a thorough assessment of their pharmacokinetic and pharmacodynamic properties for it to be represented as oral therapeutic proteins [23].…”

Re-Assessing PK/PD Issues for Oral Protein and Peptide Delivery

“…Simultaneously, a plethora of approaches to achieve oral delivery of biopharmaceuticals have been described by both academic and industrial scientists using a variety of preclinical models [ 3 ]. Markets for oral biopharmaceuticals have been predicted to be worth $43.3 billion USD by 2024 [ 4 ]. A PubMed search of the terms “oral protein peptide delivery” and “oral peptide delivery” identifies thousands of entries.…”