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Oral Delivery

Innovations in Oral Peptide Deliver y

a report by

Martin Werle

Department of Pharmaceutical Technology, Leopold Franzens University Innsbruck

The oral delivery of therapeutic peptides and proteins has always been a significant challenge for pharmaceutical technologists. Several barriers encountered with the oral route are responsible for comparatively poor plasma levels of orally administered peptide drugs. The most important obstacles are the enzymatic barrier caused by luminally secreted and membrane-bound proteolytic enzymes and the absorption barrier, which consists of the mucus layer covering gastrointestinal (GI) mucosa, the mucosa per se and transmembrane located efflux pumps such as P-glycoprotein. Of course, the bioavailability of orally administered peptides heavily depends on the physicochemical characteristics of the peptide drug, such as solubility, size and charge. In recent years, there has been much progress in the development of non-invasive peptide drug delivery systems; in particular, the potential of pulmonal delivery for peptides such as insulin has been demonstrated. However, due to the obvious advantages of oral peptide delivery, including high patient compliance and ease of administration, this delivery route is by far the most favoured. Moreover, oral drug delivery represents an estimated US$25 billion market. Currently, only a few oral peptide formulations are on the market, including a microemulsion for cyclosporine and desmopressin tablets. Promising oral peptide delivery technologies have been developed by various drug delivery companies, such as Emisphere, Merrion Pharmaceuticals, Nobex, Spherics and ThioMatrix. Among these technologies, Emisphere offers a wellestablished permeation-enhancing technology. Its Eligen® technology is based on auxiliary agents that are supposed to act as carriers that transport peptides across the intestinal mucosa. The technology uses the body's natural passive transcellular transport process. Even large or highly charged molecules can be transported across cell membranes. In theory, the delivery agent dissociates from the drug molecule after crossing the membrane and the peptide drug reestablishes its natural conformation and returns to its


therapeutically active state. It has been demonstrated for certain drugs that this process does not involve chemical modification of the drug molecule and the integrity of cell membrane and cytoskeletal structure are maintained. Emisphere has established a library with more than 4,000 potential delivery agents, of which N-[8-(2-hydroxybenzoyl)amino] caprylate (SNAC) is perhaps the most popular. SNAC is used for the oral administration of heparin and insulin. Other agents delivered with Emisphere technology are parathyroid hormone (PTH) 1-34, human growth hormone (hGH) and salmon calcitonin. Emisphere has also demonstrated oral delivery of over 60 other compounds in animal models. Currently, several clinical trials (phase I­III) using the Eligen technology are in progress. Besides independent development, Emisphere is also developing formulations with partners such as Novartis and Roche. Another strategy for the oral delivery of peptides is Nobex technology. In brief, conjugated drug­ polymer molecules are created by attaching low molecular weight polymers at specific sites. These oligomers have an amphiphilic character, comprising a fat-soluble alkyl chain and a water soluble polyethylene glycol (PEG) part. Declared advantages are that the conjugated drug­polymer is not degraded as readily by enzymes in the body compared with the drug in its native form. Moreover, the conjugated drug is absorbed more efficiently across the GI wall than the drug in its native state, due to its enhanced diffusion through both the water and fatty portions of cells and tissues that make up barriers to absorption along the GI pathway and into the bloodstream. Another advantage is that modifications to the molecule can be designed to favourably alter the drug's pharmacokinetics. The core business of Nobex is the development of oral insulin and B-type natriuretic peptide (BNP) formulations. The postprandial plasma glucose level in human volunteers with type 2 diabetes decreased after oral administration of Nobex hexyl-insulin monoconjugate 2 (HIM2) in comparison with the oral placebo.

Martin Werle has been working since 2004 at the Department of Pharmaceutical Technology, Leopold Franzens University Innsbruck in the research group of Professor Andreas Bernkop-Schnürch. He has published original research papers, review articles and book contributions on oral drug delivery. The main focus of his research is the development of polymeric delivery systems for the administration of therapeutic peptides and proteins.


Oral Delivery

The efficacy of mucoadhesive polymers for the oral delivery of peptide drugs has been demonstrated. Technologies based on such mucoadhesive polymers have been developed by Spherics and ThioMatrix. The polymeric drug delivery systems of Spherics are based on poly(fumaric-co-sebacic) anhydride. Moreover, Spherics has developed phase inversion nanotechnology (PIN), which generates drug nanoparticles (less than 2µm). Phase I studies have recently been completed successfully with the biopharmaceutical classification system (BCS) class IV drug paclitaxel and the class II drug acyclovir. However, the technology is generally applicable for all classes of the BCS. Mucoadhesive polymers, like the SpheromersTM marketed by Spherics, increase residence time in the desired region of the GI tract by increasing adhesion of dosage forms to mucosal tissues. The polymers thereby extend the window for drug absorption from the GI tract into the bloodstream. Also, the targeting of specific sites within the GI tract to treat GI diseases can be achieved. Moreover, PIN technology can encapsulate micronised particles with bioadhesive polymers to further improve drug uptake. The mucoadhesive polymers developed by ThioMatrix are synthesised by the covalent attachment of low molecular weight thiol groupbearing compounds such as cysteine or glutathione to polymers such as chitosan or poly(acrylic acid). These patented thiolated polymers, or so called thiomers, exhibit up to 100-fold improved mucoadhesive properties in comparison with the unmodified polymers. The mucoadhesive mechanism is based on the formation of disulfide bonds between the thiol groups of the thiomers and disulphide-rich domains of the mucus. Moreover, permeation of BCS class III drugs is improved by a reversible opening of tight junctions. As discovered recently, the technology is also useful for drugs taken up by the trans-cellular route, because of the ability of thiomers to inhibit efflux pumps. Furthermore, studies with thiolated polycarbophil also demonstrated an inhibitory effect of this thiomer towards intestinal proteolytic enzymes. Thiomers are able to reduce calcaemia mediated by oral administration of calcitonin. ThioMatrix is focusing on oral delivery systems for hGH, insulin and calcitonin. Several delivery systems for other drugs are developed in co-operation with big pharmaceutical companies. The drug delivery systems of Merrion Pharmaceuticals are based on a GI permeation enhancing technology. This technology does not require chemical modification of the active drug, and clinical safety studies have shown that the penetration-enhancing


effects are rapidly reversible. Co-administration of medium chain fatty acids such as caprylate (C8) or caprate (C10), which have been known for decades as potential permeation enhancers, improves oral bioavailability by a reversible opening of tight junctions. Merrion Pharmaceuticals is using this wellestablished technology, providing oral bioavailabilities of 5­13% for compounds that normally have bioavailabilities below 1%. Besides the above-discussed technologies, other approaches to delivering therapeutic peptides and proteins by the oral route include micro- and nanoparticles, polymer­enzyme inhibitor conjugates, targeting of the colon where proteolytic activity is relatively low, co-administration of low molecular weight permeation enhancers and/or enzyme inhibitors, and the use of patch systems. The efficacy of micro- and nanoparticluate delivery systems, composed of various polymers including chitosan, PEG, and polymethacrylic acid-chitosan-PEG, to improve bioavailability of orally administered peptides has been demonstrated in various studies. Further optimisation of nanoparticles by adding functional features can lead to even more improved peptide plasma levels after oral administration. Takeuchi et al. and Garcia-Fuentes et al. have developed nanoparticles with mucoadhesive coatings, suitable for the delivery of peptides such as calcitonin. The co-administration of solubility enhancers including Myrj or cyclodextrins can also improve oral peptide uptake. Polymer­enzymeinhibitor conjugates have been evaluated regarding their potential to reduce enzymatic peptide degradation by GI enzymes. The coupling of pepstatin to chitosan, for example, led consequently to an enhanced calcitonin uptake in vivo. The advantages of polymeric auxiliary agents in comparison with unbound agents are that they are not absorbed and therefore systemic toxicity can be excluded. Moreover, mucoadhesive polymer­inhibitor conjugates are less affected by dilution during GI passage than low molecular weight agents, so that lower amounts of the polymeric auxiliary agent can be used. In conclusion, due to the progress in the development of oral drug delivery systems in recent years, several therapeutic peptides might be administered via the oral route in the near future. Another important factor in this context is that by using novel technologies, production costs for peptides and proteins have already been minimised. The chances of novel oral drug delivery technologies for a market launch will depend on several factors such as efficacy and safety, as well as economic reasons. A version of this article containing references and three graphics can be found in the Reference Section on the website supporting this briefing (



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