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Insulin Pills Finally in Clinical Trials

Jun 9, 2010

After years of research and anticipation, insulin pills that could make it easier for millions of patients worldwide to manage their diabetes are moving ahead in clinical trials.

Drug manufacturers have tried for years to develop oral insulin without much success. Insulin is a peptide hormone that people with diabetes currently take by injection to bring their blood sugar to within normal levels. But doing so requires uncomfortable, inconvenient injections that can make patients reluctant to use the drug frequently enough to adequately control their blood sugar. An oral form of insulin could help solve this problem. However, stomach acids and enzymes easily destroy insulin and other protein-based drugs. Scientists have had difficulty finding an effective way to eliminate this problem.

They’ve responded to this challenge by developing special coatings for insulin pills that prevent stomach acids from destroying them. Scientists also are using additives that make it easier for the intestine to absorb large molecules like insulin. After years of setbacks, signs of success may be at hand. Several insulin pills are now in various stages of clinical trials, and proof of concept may allow them to move into late-stage and more rigorous clinical testing. Only time will tell, however, whether these much-anticipated pills will make it to the market.

Among developers, India’s Biocon is the furthest along, with a technology acquired in 2006 from now-defunct Nobex. In scientific publications, Biocon scientists have described the firm’s candidate, IN-105, as an insulin molecule conjugated to a short-chain polyethylene glycol derivative.

Put in a tablet, IN-105 retains similar activity to insulin alone, withstands degradation, and is consistently absorbed, according to Biocon. Results from a Phase III clinical trial in India are expected in September. In late 2009, Biocon applied to the U.S. Food & Drug Administration to allow it to start clinical trials.

Solid oral forms could have efficacy and safety advantages, too. Insulin delivered this way, unlike injected forms that circulate systemically, is believed to behave more like the body’s own. Natural insulin is secreted by the pancreas and taken up by the liver, which stores and metes it out when needed. Engineered for release in parts of the small intestine just past the stomach, solid oral insulin can be taken up from there by the portal vein and delivered to the liver.

Getting the insulin through the stomach via an enterically coated tablet or capsule, which is stable under acidic conditions, is the relatively easy first step. The drug isn’t released until the pill reaches the small intestine and starts to dissolve at higher pH. Sometimes enzyme inhibitors are added to stave off digestion. The overall goal is keeping as much insulin as possible intact for eventual absorption.

The harder second step is getting a large, hydrophilic protein past the intestinal walls. Although proteins find it hard to diffuse across the hydrophobic lipid membrane or through epithelial cells in the wall, they can conceivably be squeezed between cells. To wedge open tight intercellular junctions, developers add permeability or absorption enhancers to formulations.

Enhancers include oils, fatty acids, surfactants, and mucoadhesive or other polymers. Formulators are loath to give specifics, but they will disclose that the materials are typically off-the-shelf and already approved for use as food additives or in drug formulations. Using physical blends of enhancers with a known drug means that the safety profiles of the components are unchanged for regulatory purposes. In contrast, any chemical modifications create new entities that have to be tested.

With products moving into clinical trials, among the unanswered questions are ones about the long-term effects of insulin and the accompanying materials. Insulin induces cell division, and researchers are concerned that it might be associated with an increased risk of certain cancers. Companies working in this area generally believe that nothing but the drug and enhancers pass through the intestine.

Results from studies with oral insulins will be presented at the American Diabetes Association’s 70th Scientific Sessions in Orlando, Florida later this month.

Chemical & Engineering News June 2010.