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Cover Story

May 31, 2010
Volume 88, Number 22
pp. 27 - 30

Nicer Than Needles

Delivering biologic drugs orally, instead of by injection, calls for tricking the human body

Ann M. Thayer

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SWEET SPOT Many companies have been trying to convert insulin from an injectable drug into pill form. iStock
SWEET SPOT Many companies have been trying to convert insulin from an injectable drug into pill form.

To the chagrin of the biopharmaceutical industry, the human body is designed to digest proteins. Acids and enzymes in the gastrointestinal tract will chew up a valuable therapeutic protein as easily as they’ll tear into a bite of steak. To avoid this fate and reach the intended target, most protein pharmaceuticals are formulated for injection or intravenous infusion. As a result, large amounts of drug tend to be administered less often.

For biologic drugs such as insulin that must be taken frequently, a more user-friendly delivery route would improve patient compliance and limit complications. Easy to take, handle, and store, solid oral dosage forms are considered so desirable that many companies have attempted to put proteins into pills. To date, however, none has reached the market.

Most strategies involve chemically modifying or physically shielding the protein molecule as a first step to protect it. If the protein can slip past the stomach this way, it must next plow through nearly impenetrable intestinal barriers. Even after that, it might have to survive metabolism elsewhere in the body.

With so much working against them, many oral forms of insulin have shown limited bioavailability. In absolute terms or compared with injections, only a small fraction of the original dose ends up circulating in the body. This is a problem because maintaining adequate and consistent insulin levels, within a limited therapeutic window, is critical in safely managing diabetes.

Many companies—some of which are no longer in business—have started and abandoned programs to develop oral insulin. Generex Biotechnology is one firm that has achieved limited success. In India and a few other countries, it sells an aerosolized liquid formulation absorbed in the mouth.

Meanwhile, the big diabetes drug firms—Eli Lilly & Co., Novo Nordisk, and Pfizer—tried making insulin inhalable, only to be hugely unsuccessful. They all halted very late-stage candidates or, in Pfizer’s case, launched and then withdrew a product (C&EN, May 12, 2008, page 24). Although the big companies are chastened, several small firms seem undaunted as they tackle making pills and capsules.

“I think it is possible, depending on what you want to achieve and how you approach it,” says Miriam Kidron, chief scientific officer (CSO) of Oramed Pharmaceuticals. “I don’t know when it will be, but at the end of the day, there will be a few oral insulins for the patients who need them.”

Oramed and other small companies clearly have business incentives. The global diabetes market exceeds $30 billion annually, with insulin sales accounting for about half of that, according to the market research firm IMS Health. If new solid doses can perform at least as well as, if not better than, existing products, they might promise new sales, lower costs of delivery, and extended patent life. Fortunately for drug developers, recombinant production can make enough insulin inexpensively for the larger doses required in oral forms.

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.

Ireland’s Merrion Pharmaceuticals has a technology to enhance gastrointestinal permeation that it acquired in 2003 from Elan Corp. Called GIPET, the method uses enhancers that are blended with the drug and formed into an enterically coated tablet. After being released in the first section of the small intestine, the enhancers form micelles to help transport the drug.

GIPET will also work with peptides, macromolecules, and small-molecule drugs. “We have seen quite a bit of human clinical data with our technology,” says John Lynch, Merrion’s chief executive officer. “Well over 30 different compounds have been tested, and we see very significant increases in the bioavailability, which can be 10-, 20-, or 30-fold versus what would happen if you didn’t have the enhancers present.”

Although the approach is simple, proof of principle and positive data are generating interest, Lynch says. Merrion began working with Novo Nordisk in 2008 on solid oral forms of insulin analogs. In late 2009, Novo started the first Phase I clinical trial. The companies signed another agreement in early 2009 to develop solid oral glucagon-like peptide-1 (GLP-1) analogs, a new therapy for controlling blood sugar levels in people with type 2 diabetes, and Novo began a Phase I study last month.

Novo Nordisk is also working with New Jersey-based Emisphere Technologies on oral GLP-1 analogs. In January, Novo began a Phase I trial of the first candidate based on Emisphere’s Eligen technology. “We still have a long road with many challenges ahead of us before an insulin pill or GLP-1 pill becomes a reality,” said Peter Kurtzhals, Novo’s head of diabetes research, at the time. “But with the progress we have made so far, I am convinced it is only a matter of time.”

After about a decade of work, Emisphere completed its own Phase II study of an oral insulin tablet a few years ago. In reviews of the field, experts point out that Emisphere never published the full results and that there were problems in how the trial was conducted. Emisphere now focuses on using its technology, which includes more than 4,000 carriers, to formulate a range of biologic drug/carrier complexes. The agents are said to facilitate absorption by altering the conformation and lipophilicity of a drug, but they do not modify it chemically or disrupt the intestinal wall.

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. Merrion’s work, Lynch says, “has shown that any effects on the intestinal membrane are extremely transient.”

“What you are looking to do is to get the drug absorbed in sufficient quantity to make a product viable,” Lynch explains. Another goal is limiting absorption variability, which can be caused, for example, by interactions with food. Tests with GIPET, he says, have shown consistent and reproducible uptake of the drug.

Likewise, Oramed, which is based in Israel, hasn’t seen problems arise in lab animals exposed for many years to its formulation, according to CSO Kidron. In human clinical studies, the company has been testing enteric capsules containing 8 mg of insulin and a mix of absorption enhancers.

Although the dose is two to three times the amount that might be injected daily, this larger amount is not unusual for oral forms, Kidron explains. Increasing the insulin dosage is one way to avoid variability at different times for a given patient. Even with injected insulin, the variability can be large, she points out. At the American Diabetes Association meeting scheduled for June, Oramed plans to present results for a formulation that doesn’t show timing or food effects, Kidron says.

Earlier this month, Oramed reported results from a Phase IIb trial in South Africa. Along with being found safe, its ORMD-0801 showed a relevant clinical impact on insulin and glucose levels. “We hope within about half a year to be able to do a Phase II study under an Investigational New Drug Application in the U.S.,” Kidron says.

An alternative to coaxing insulin through intercellular spaces is to transport it across intestinal cells via carriers. Along with lipid-based systems, polymer nanoparticles are one such vehicle, but they often need help getting where they should go. To do this, Dallas-based Access Pharmaceuticals uses the body’s own vitamin B-12 uptake mechanism.

In the Access system, insulin-containing polymer nanoparticles coated with vitamin B-12 analogs attach to a glycoprotein made in the stomach called “intrinsic factor.” This factor then binds to receptors in part of the intestine. Appearing to be just the vitamin, the entire Trojan horse complex is pulled into circulation. Physical properties of the nanoparticle keep it intact until it reaches the bloodstream, where it releases the insulin.

“Ours is the first mechanism that actually uses the body’s own process to trick it and get the insulin through,” Access CEO Jeffrey B. Davis says. On the basis of animal studies of its oral insulin, the company claims to see a pharmacological response equivalent to 80% of that achieved by injection.

Access reports that collaborators have evaluated the technology and confirmed these results. Davis believes that this is an important step in convincing a jaded R&D community that solid oral forms can work.

Because small and large mammals absorb vitamin B-12 in the same way, Davis is confident about eventual success in humans. “We’re trying to get a proof of concept in humans as quickly and inexpensively as possible because we are a small biotech company,” Davis says. “So we will probably look to do that outside the U.S.”

In March, Access launched a clinical development program with BioRasi, a Florida-based contract research firm that has experience in the diabetes area and works with organizations in Russia and Central Europe. BioRasi will follow international guidelines to eventually support regulatory submissions in Europe, Japan, and the U.S.

Despite the advances made so far, Davis admits that he wishes Access had tackled something other than insulin first. “People are very snakebit about someone saying ‘I can do oral insulin,’ because so many people have failed at it,” he says.

For the small companies developing oral insulin, proof of concept for their technologies will help demonstrate commercial potential and, they hope, rejuvenate interest in the industry. Many hope that they will attract large partners, not just for insulin but also for a host of biologic drugs that might be transformed into easier-to-take and better-to-use solid dosage forms.

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society
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