Technology

Reality check on oral insulin

Though Big Pharma seems to have given up on oral insulin, a few biotechnology companies continue research in this direction. Express Pharma reviews the research

Divya Pamnani

About 194 million people worldwide, or 5.1 percent, in the age group 20-79 were estimated to have diabetes in 2003. This estimate is expected to increase to some 333 million, or 6.3 percent of the adult population, by 2025. These statistics emphasise the need for enhanced insulin therapy, and oral insulin could be the next breakthrough in decades of insulin research.

Research in oral insulin appears to be one step closer to being available to people who need to take multiple daily injections of insulin, which is currently the standard treatment for insulin-dependent diabetic patients. In spite of numerous research road blocks, an oral insulin delivery system continues to evolve, which means that people with diabetes could soon forgo injections.

Why oral insulin?

Insulin injected subcutaneously at least twice a day (sometimes several injections a day) being a part of a diabetic's everyday life, can be extremely harrowing. The strict regimen diabetics must follow this mode of insulin treatment as it affects their lives to a great degree. Inherent disadvantages include local pain, itching, allergy, and insulin lipodystrophy around the injection site. Insulin lipodystrophy results in atrophy of fats at the frequent sites of insulin injection. This can be observed as irregular depressions on the skin. Lastly, clinical trials have shown that even on injectable insulin treatment, a significant percentage of patients fail to attain lasting gylcaemic control due to non-compliance.

Oral insulin—making needles needless—is gaining widespread prominence, to offset the above mentioned disadvantages. The oral route is considered to be the most acceptable and convenient route of drug administration for chronic therapy. Due to knowledge explosion in the biotechnology industry, extensive investigations are being conducted to achieve successful control of blood glucose by the oral delivery system.

Research challenges

One of the major challenges of oral insulin research has been that insulin breaks down in digestive liquids to a degree that it becomes less useful than with injecting it. The absorption of insulin is reduced in the gastrointestinal (GI) tract, due to the degradation by proteolytic enzymes (protein digesting) like pepsin. Further, the process of 'first pass metabolism' leads to a still further reduction in the bioavailability, and therefore, reduced pharmacological action of insulin. First pass metabolism is the process of detoxification that happens in the liver—contents of the small and large intestines enter the liver through the portal vein to eliminate remaining traces of toxic materials. Thus, due to enzymatic action and the first pass effect, drugs get metabolised, and are less effective.

Another oral insulin research road block is that rate of absorption from different regions of the intestine is not uniform. The cellular morphology of the intestines changes from region to region, and the proteolytic activity of protease gradually decreases from the duodenum to large intestine. Researchers suggest that there may be an optimal site for insulin administration in the small intestine, and that selective release of insulin directly into the mid-jejunum (in the small intestine) would help to protect the insulin from the gastric and pancreatic enzymes.

Factors in the oral insulin delivery route

In the last three decades of oral insulin research, the following possibilities have been attempted and explored, either singly or in combination:

• Using antiproteolytic agents to protect insulin from enzymatic degradation
• Promoting the gastrointestinal absorption of insulin through simultaneous use of a multitude of different penetration enhancers
• Improving the stability of insulin by chemical modification
• Enhancing the contact of insulin with the mucous membrane lining of the GI tract using bioadhesive delivery systems
• Advancing the bioavailability of insulin using carrier systems such as microspheres and nanoparticles.

Recent developments in the administration of insulin

Oral insulin pills: Insulin administration in the form of a pill has always been an attractive concept in research. Due to numerous limitations of this mode of insulin administration, efficacy has been hard to demonstrate. Research has focused on overcoming these limitations by stabilising the degradation, improving the permeability, and adding absorption promoters to protect the insulin as it passes through the stomach.

Intranasal insulin: Intranasal insulin, taking the nasal route, exposes the mucus membrane to insulin via a nasal spray. While intranasal insulin has been shown to achieve significant decreases in plasma glucose concentrations, its bioavailability is poor, and the dose needed to reach glycaemic control markers is significantly higher than for insulin that is administered subcutaneously.

Oral spray: An alternative to injected insulin that is currently being explored by researchers is a mouth spray containing insulin that would be absorbed through the lining of the mouth and throat. The liquid formulation allows the insulin to be absorbed by the mucus membranes in the cheeks, tongue, and throat. The benefit from oral spray is identical to an insulin injection in its ability to lower blood glucose levels.

Pulmonary or inhaled insulin: The inhaled insulin system delivers a dose of insulin, either in liquid or dry powder form, through the mouth, directly into the lungs, where it enters the blood circulation as rapid-acting insulin. With inhaled insulin, the highly permeable alveolar epithelium and large surface area of the lungs provide an effective, efficient portal for macromolecular delivery.

Skin patch: This device injects insulin through micro-needles into the epidermis, without triggering pain receptors that are present in the layer below the epidermis—the dermis. The micro-needles in the patch pass through the top most layer of the skin—stratum corneum—and administer the insulin into the epidermis, lying below the stratum corneum. One problem with the patch is that insulin does not easily and effectively pass through the skin layers due to its high molecular weight. Another critical concern of the skin patch is infection. Manufacturers need to demonstrate that tiny holes made on the skin will not let bacteria and viruses in causing infection. This is still a technology in development, and proof of success is yet to be demonstrated before reaching the market.

Inhaled insulin dumped by Big Pharma

Excubera, the first version of inhaled insulin, approved by the Food and Drug Administration (FDA) in 2006, was dropped by Pfizer in less than a year of poor sales, simply because it failed to gain acceptance by patients and physicians. Exubera (recombinant human insulin with particle diameters between 1 and 5 mm) was a massive technical achievement, involving the stabilisation of the insulin molecule to make it bioavailable in the dry powder form. It was the first insulin product that did not need to be injected, so when it was approved in January 2006, after being in development for 11 years, there were high expectations. With several advances in devices to inject insulin, the Exubera inhaler, the size of a can of tennis balls, was not appreciated by patients. Not only was the inhaler too large, but dosing was difficult as well. Pen-like injectors seemed like a safer option, with pre-measured doses. Moreover, the complexities of the inhaler device with dosing required healthcare professionals to be trained. Besides the disadvantages of size, dosing and training, Exubera had a known side effect—it reduced lung function and capacity. The worst and last hit that Exubera took was lung cancer. A little over 4,500 users of the inhaler had contracted lung cancer.

After Pfizer exited the market for inhaled insulin, other Big Pharma players like Eli Lilly and Novo Nordisk also walked away from their products AIR Insulin and AERx iDMS respectively, on accounts of commercial and clinical unviability of these products. The ripples of Exubera's failure spread to other drug firms as well, who found it increasingly hard to create a market for their products.

Although a handful of small biotechnology firms continue to stay on course including Mankind Pharma (Technosphere Insulin System) and Abbott Laboratories, companies like Biocon (Bangalore), Transgene Biotek (Andhra Pradesh) and Generex Biotechnology (Canada) are moving on, investing heavily in the oral insulin delivery system research.

Biocon, Bangalore

Biocon is developing the IN-105 conjugated insulin molecule, administered as a tablet and delivered through the portal vein. This oral insulin pill has polymers added at specific locations in the B chain of the insulin to prevent insulin from getting destroyed in the stomach (insulin is made up of two polypeptide chains namely, chain-A with 21 amino acids and chain-B with 30 amino acids, which are held together by two disulfide bonds). Biocon's R&D group has successfully developed a carefully selected formulation to give consistent absorption through the intestines, delivering the glucose-lowering effect. In the clinic, this molecule has completed phase I trials and is expected to enter phase II in India later this year to illustrate proof of concept. The encouraging results of the phase Ia and Ib studies represent a pivotal hurdle crossed in the development of IN-105 as a product. IN-105 will enter phase I trials in Europe towards the end of the year.

Generex Biotechnology, Canada

Oral-lyn is the company's proprietary oral insulin spray product. The liquid formulation is absorbed into the body by the lining of the inner mouth using the company's proprietary RapidMist device. Since it is buccally absorbed, no insulin is deposited in the lungs by the Oral-lyn RapidMist. August 2007 saw the commercial launch of Oral-lyn in the Indian market. Generex Biotechnology entered into Master Product Licensing and Distribution Agreement of Oral-lyn with Shreya Life Sciences, the fourth largest distributor of insulin in India. In April 2008, Generex entered into a similar agreement for the distribution of Oral-lyn in China, Hong Kong, and the following additional countries: Indonesia, South Korea, Malaysia, the Philippines, Singapore, Thailand, and Vietnam. Presently, Generex Oral-lyn is in phase III clinical trials at several sites around the world—US, Canada and Ukraine.

Transgene Biotek, Andhra Pradesh

Transgene has developed an oral delivery technology which combines several oral delivery approaches into a single drug delivery system. Unique in its approach, this technology involves using biodegradable novel polymeric nanoparticles loaded with insulin as a new carrier to ferry the insulin across the intestinal epithelial tissues. Nanoparticles are solid spherical particles with a size range of 10 and 1,000 nm containing dispersed drugs. Transgene has attempted to improve the intestinal absorption of insulin and other peptides. The technology has been well proven in animal models, and human clinical studies are in progress.

It looks like oral insulin is a reality—it's simply a matter of when. Research and clinical trials look promising. Drug companies are obviously interested in the potential of oral insulin to net a massive share of the market, and therefore, investment in research is substantial and ongoing. Biocon, Transgene Biotek and Generex Biotechnology have proven to be insightful in the race to enhance the treatment of diabetes, and are definitely ahead of the pack.

(The author has done her Bachelor of Science in Psychology and Biology at the University of Texas at Austin. She can be contacted at pamnani.divya@gmail.com)