The dream of an insulin that can be taken by mouth has long been with us, and many attempts have been made to realize it. Quite apart from avoiding the need for insulin injection, oral insulin would have the potential advantage that insulin absorbed from the gut would pass directly into the portal circulation, unlike subcutaneous injections which pass into the systemic circulation. There are however many technical difficulties associated with oral insulin, including the physical challenges of exposure to gastric acid and proteolytic enzymes, and limited absorption across the intestinal mucosa. Bioavailability is likely to be low (with associated high costs for the insulin) and variable absorption might limit the prospects of good glucose control. Many efforts have been made to solve these problems, mostly centered around ways of protecting insulin from degradation and promoting its absorption. Most are of historical interest only, but nanoparticle technology continues to hold out some promise.
Preventing degradation of insulin
A range of physical barriers have been employed to protect insulin as it transits the stomach. These include tablet formulations, capsules, and various types of protective gel coatings. More recently, nanoparticle technology has been applied to the problem. The difficulty of protecting insulin in the stomach while ensuring its timely release in the intestine has been a particular challenge. Once this has been achieved, however, it must still be protected from enzymatic degradation, and a range of enzyme inhibitors and other excipients have been included in the formulation for this purpose.
Tablets and Capsules
Chitosan-4-thiobutylamidine tablets contain insulin packaged with enzyme inhibitors covalently linked to enzyme inhibitors. Chitosan is a complex polysaccharide obtained from the shells of shrimp and other crustaceans which degrades rapidly in an acidic environment, allowing release of insulin and associated molecules on passage through the stomach. Trials in rats have been considered promising.
CODES is a formulation designed to deliver insulin into the colon, with multiple protective coatings to ensure it arrives there intact. Once in the colon a mucous gel is formed which might potentially allow sustained insulin release.
Eudragit S1000 is an anionic polymer used for intestinal drug delivery because it has the property of remaining insoluble in an acidic environment and soluble in an aqueous environment at higher pH. Tests suggest that this system achieves ~12.5% of the effect of injected insulin
Capsulin is a formulation which has reached phase 2a studies in humans and is reported to produce increased insulin levels in the circulation 30-120 minutes after ingestion
ORMD-0801 is an enteric coated insulin plus excipients in development for use in type 1 and type 2 diabetes.
Comment: Although several of the above and other agents are in early clinical development, none seems likely to mount an effective challenge to subcutaneous insulin.
Lipid-based insulin nanoparticles
Solid lipid nanoparticles have been developed as an alternative delivery system, but achieve low bioavailability (5-7%) as compared with injected insulin
Liposomes are intracellular organelles which can be induced to take up insulin and have been tested on many occasions since the first proof of principle in 1976. As the long latency period suggests, the technical challenges of this approach have yet to be overcome.
Polymer-based insulin nanoparticles
Chitosan (see above) has been the most widely tested polymer, not only because of its varying solubility in acid and alkaline solutions, but also because it adheres to the mucous coat of the intestine, facilitating uptake of insulin. Alginate and dextran are potential alternatives.
The use of nanoparticles also lends itself to the possibility of sustained-release formulations of insulin, potentially allowing longer-lasting insulin delivery.
A further potential application is to attach a ligand to the nanoparticles, allowing them to bind to receptors on enterocytes
Summary and Conclusions
At present oral insulin delivery remains something of a dream. Many companies and entrepreneurs have entered this arena, only to drop out at a relatively early stage, and often for unstated reasons. There is no question that insulin taken by mouth and protected from acid degradation in the stomach is bioactive, and that a number of the strategies outlined above can enhance this bioavailability. Unfortunately, this remains a small fraction of the bioavailability of injected insulin. A further problem is that of cost, since the manufacturing costs of insulin would need to be substantially reduced to make oral insulin a commercial reality. The only certain future for oral insulin is that people will continue to try and make it.
^ Fonte P et al (2013). Oral insulin how far are we? J Diabetes Science & Technology 7(2):520-531
^ Katsuma M et al (2006). Effects of absorption promoters on insulin absorption through colon-targeted delivery. Int J Pharm 307(2):156-62
^ Hosny EA et al (2002). Oral delivery of insulin from enteric-coated capsules containing sodium effect on relative hypoglycemia of diabetic beagle dogs. Int J Pharm 237(1-2):71-6
^ Patel HM, Ryman BE (1976). Oral administration of insulin by encapsulation within liposomes. FEBS Lett 62(1):60-3
^ Damge C et al (2008). Nanoparticle strategies for the oral delivery of insulin. Expert Opin Drug Deliv 5:45-68