Newsletter: October 2016

Successful administration of therapeutic proteins such as insulin via the oral route has long eluded the drug delivery community. A variety of factors, both physical and physiological, have hindered the myriad approaches to increasing the bioavailability of orally administered therapeutic proteins, including: 1) pre-systemic (along the gastro intestinal tract) degradation by enzymes; and 2) poor penetration of the intestinal mucosa (mucus layer) and epithelium (intestinal wall).

Even when bypassing the harsh, acidic environment of the stomach, the intestines pose significant obstacles to systemic uptake. For example, the lining of the gastrointestinal tract has a thick wall of epithelial cells covered by a layer of polysaccharides and mucus.

Insulin is a highly hydrophilic drug with a high molecular weight. This implies that insulin is highly soluble in water and it is extremely difficult for it to cross the mucus layer and small intestinal wall due to its high molecular weight. Nonetheless, the oral route of administration is often preferred due to the easy accessibility of the large surface area available for absorption to the systemic circulation. Furthermore, the pharmacological rationale for administering specific proteins such as insulin via the oral route supports this approach, as the oral delivery of insulin results in absorption directly to the liver (the target site) by hepatic portal circulation, before it reaches the peripheral tissues.

Indeed, when the drug of interest must be administered repeatedly, the oral route inevitably becomes the route of choice for patients since it is painless and convenient. The main challenge is to improve the oral bioavailability to be higher than 1% as currently, compared to injections, oral doses of proteins in delivery systems described tend to be very high whilst the bioavailability remains invariably very low.

New approaches are mostly driven by the necessity to design an approach that not only protects the protein/peptide from enzymatic degradation but also aids in enhancing its absorption without altering its biological activity. Some of the emerging oral peptide or protein drug delivery strategies in preclinical or entering clinical trials are based on modified nanoparticles. NOD Pharmaceuticals Inc are currently conducting Phase II clinical trials with oral insulin and exenatide mucoadhesive nanoparticles, and NanoMega Corp have encapsulated insulin in chitosan shelled gamma g-PGA nanoparticles.

Other strategies that are in advanced stages in clinical trials include the Axcess delivery system developed by Proxima concepts based on an oral capsule that contains the protein or peptide as well as undisclosed GRAS excipients such as permeation enhancers and solubilisers to enhance transcellular absorption. Capsulin is an enteric-coated insulin capsule developed by Diabetology, Ltd, based on Proxima´s proprietary Axcess delivery system and is currently under Phase III clinical trials. On the other hand, Oramed is currently using its Protein Oral Delivery (POD) technology to develop an insulin pill, now in Phase IIb clinical trials. POD is an enteric-coated capsule containing an oily suspension of the peptide drug, an enzyme inhibitor (soy bean trypsin inhibitor, aprotinin) and an absoprtion enhancer (ethylenediamine tetraacetic acid (EDTA) or bile salt), in omega-3 fatty acids. Results from Phase IIa clinical trials showed that POD technology significantly reduced glycemia in a small group of type 1-diabetes patients and this technology was safe and well tolerated.

We designed nanocapsules based on cell penetrating polymer, capable of encapsulating insulin, protecting it from the harsh intestinal environment and promoting its absorption across the epithelial wall. In vitro studies in simulated intestinal media (with and without enzymes) and Caco-2 cells, including in vivo studies in rats, highlighted the potential for these polymer-based nanocapsules to interact with intestinal mucosa and promote the absorption of the peptide across the intestinal epithelium. This was attributed to the presence of an oily core, stabilising and cell penetrating surfactants.

To achieve oral insulin delivery, greater understanding of their gastro intestinal stability and permeability is needed. This will enable targeting of optimal gastro intestinal regions for uptake and improved formulation selection. There have been very few oral insulin formulations that have been clinically trialled, compared with all the delivery strategies that have been developed and tested in vitro and in animals. More trials in humans are needed to increase the likelihood of oral delivery success.