Research review paperA review of advanced oral drug delivery technologies facilitating the protection and absorption of protein and peptide molecules
Introduction
The oral delivery of proteins and peptides, although a highly attractive approach, remains a significant challenge in drug delivery technology, as a result of their unfavorable physicochemical properties (Catnach et al., 1994, Hamman et al., 2005, Park et al., 2011). Administering drugs by the oral route is preferred due to its improved convenience and patient compliance (Brayden and O'Mahony, 1998, Park et al., 2011). However, oral drug delivery can be particularly challenging when considering the variations that occur in the absorption of a molecule due to interactions with gastric contents/secretions, membrane permeability, intestinal transit and gastric emptying. This is particularly with respect to the delivery of sensitive proteins and peptides (Marques et al., 2011). Therapeutic proteins and peptides are gaining increased popularity, owing to advances in biotechnology that enable them to be the molecules of choice for an assortment of diseases (Chin et al., 2012, Park et al., 2011). The high specificity and activity of proteins and peptides make them applicable for targeted delivery in clinical practice (Brayden and O'Mahony, 1998, Chin et al., 2012, Park et al., 2011). The new 2013 Pharmaceutical Research and Manufacturers of America (PhRMA) report on “Biologic Medicines in Development” identified over 900 protein and peptide-based medicines in development, targeting more than 100 diseases, of which 353 for cancer and related conditions, 187 for infectious diseases, 69 for autoimmune diseases and 59 for cardiovascular diseases. This significantly increases the demand and focus towards achieving effective and simple routes of delivering proteins and peptides via the oral route.
Conventionally, therapeutic proteins and peptides are administered intravenously, subcutaneously or intramuscularly since the oral route of administration may result in degradation in the gastrointestinal tract (GIT) (O' Connor, 2009, Schiffter, 2011). Although significant progress has been made towards the development of oral delivery systems for proteins and peptides, the field is limited by the low membrane permeability of these high molecular mass compounds, as well as their hydrophilicity, instability and rapid enzymatic degradation in the GIT (Camenich et al., 1998, Donovan et al., 1990, Park et al., 2011). Proposed technologies and approaches targeting the complications in the oral delivery of proteins and peptides although useful in some instances, nevertheless hold limitations that enable successful delivery (Park et al., 2011).
Therapeutic proteins and peptides have gained a significant market interest owing to their increased development and applicability to multiple disease conditions (Chin et al., 2012, Park et al., 2011). Consequently, advancements towards successful oral delivery of proteins and peptides through protection and increased absorption remain an active area of research and researchers have intensified their research towards achieving this goal (Chiasma Inc.; Cosmo Pharmaceuticals, Inc.; Diabetology Ltd.; Emisphere Technology, Inc.; Enteris BioPharma, Inc; Merrion Pharmaceuticals, Ltd.; Oramed Pharmaceuticals, Inc.; Proxima Concepts, Ltd; Tarsa Therapeutics, Inc.). This review article summarizes the major challenges facing oral protein and peptide delivery as well as the various attempts at overcoming these challenges. Current and new technologies within this dynamic field of research will be discussed, including the potential benefits of each technology and possible limitations that exist. Potential for improvement is a key focus in the development of new formulation strategies and technologies.
Section snippets
The gastrointestinal barrier: a physical and chemical impediment to oral protein and peptide delivery
The GIT epithelium acts as a physical and chemical barrier towards the absorption of proteins and peptides (Antunes et al., 2013, Lee, 2002). The mucosal surface of the GIT is a large interface that is protected by a monolayer of epithelial cells, connected by tight junctions that provides an effective barrier against the absorption of proteins and peptides and thus, represents a physical gatekeeper that selectively restricts the entry of large molecules into the systemic circulation (Antunes
Potential sites for non-parenteral delivery of proteins and peptides
Possible non-parenteral administration routes for the delivery of protein and peptides include the nasal, buccal, vaginal, rectal, transdermal, pulmonary, ocular and oral routes of delivery (Antosova et al., 2009, Zhou and Li Wan Po, 1991). The parenteral administration of proteins and peptides is necessary for achieving a therapeutic outcome. However, low patient acceptability and tolerance towards continuous intramuscular, intravenous or subcutaneous injections have led to poor patient
Current approaches employed for the oral delivery of proteins and peptides for enhanced GIT absorption
Numerous strategies have been investigated in an effort to effectively deliver proteins and peptides via the oral route (Fogueri and Singh, 2009). Most of these systems target the GIT barrier in an attempt to overcome its restrictive nature and subsequently increase the oral bioavailability (Brown, 2005, Fogueri and Singh, 2009). Enteric coating has also been used to enable protection of the protein or peptide from pepsin digestion in the stomach, however, the reliability and efficiency of
Advanced oral protein and peptide technology platforms for clinical application
There are several oral protein and peptide technologies produced by pharmaceutical companies for application in various clinical situations (Park et al., 2011). Although most of the formulations based on these technologies are in the development phase, many have progressed to the clinical trial stage (Park et al., 2011). The technologies are summarized below, highlighting their favorable characteristics that would improve their absorption and oral bioavailability as well as their potential
Advancement in pharmacokinetic profile of peptide therapeutics through specialized platforms for clinical applications
Pharmacokinetics is an essential scientific discipline that governs applied therapeutics (Tripathi, 2013). The study of the Absorption, Distribution, Metabolism and Excretion (ADME) of proteins and peptides from drug delivery platforms is a key pharmacokinetic parameter that determines the response of the body towards the incorporated macromolecules (Tripathi, 2013). Fundamental pharmacokinetic information is required to improve the pharmacodynamic response (Tripathi, 2013). Thus, a critical
Conclusions and future prospects
Proteins and peptides display an increasingly important role as therapeutic agents for the treatment of various diseases (Zhou, 1994). Thus, improved non-parenteral delivery technologies are essential in ensuring optimal patient compliance and acceptance. The three major challenges with the delivery of proteins and peptides through non-parenteral routes (particularly the oral route) as assimilated in this review are their low bioavailability, susceptibility to enzymatic degradation and low
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