Drug Discovery and DevelopmentFor a drug to do its job, it must reach an adequate concentration at the site of its target, but not such a high concentration that triggers toxicity. In short, a compound needs the right bioavailability. “For today’s active pharmaceutical ingredients in development, about 90% have a huge question mark on bioavailability,” says Roger Weibel, head of bioavailability enhancement, global marketing at EMD Millipore (Billerica, Mass.). “To increase bioavailability is a major issue.”

Even some of today’s best-known drugs faced challenges in bioavailability. For example, Glivec—a revolutionary oncology drug from Novartis (Basel, Switzerland)—lacked adequate bioavailability in the very early stages of research. Through years of development, Novartis created a mesylate salt of the active compound, imatinib, and ultimately the beta crystal form of imatinib mesylate found in the approved drug that would deliver consistent, safe, and effective levels of the medicine.

To enhance the bioavailability for a wide range of compounds aimed at diverse targets, drug developers need a complete toolbox. Thinking along those lines, Weibel says, “We offer a huge range of products.”

In the many cases, lack of adequate bioavailability leads to failure in clinical trials. “Even if compounds don’t fail, their performance could be significantly enhanced,” says Conrad Winters, PhD, director, drug product development at Hovione (Loures, Portugal). Furthermore, Winters points out that increased bioavailability could trigger reduced dosages, “which means potentially minimized side effects or other drug interactions.” 

Filling the toolbox

As part of EMD Millipore’s technologies, Weibel mentions its bimodal silica, which earned a silver medal in the innovation awards at CPhI Worldwide 2012. Weibel says, “This amorphous silica—made by a special technology that we developed—and our expertise in loading drug substances to silica to enhance solubility leads to enhanced bioavailability.” 

Weibel adds, “We will share with our customers our expertise in how to load material to the silica particles and teach customers to handle the material to make sure they won’t waste time and effort.”

He also points out that EMD Millipore offers excipients to formulate orally disintegrating tablets that can be coated, counter ions like meglumine, and products for liposomal formulations and pegylating proteins.

Novozymes Biopharma increases a drug’s half-life by attaching it to modified albumin, which binds longer to its receptor, as shown in albumin’s lifecycle. Source: Novozymes Biopharma

Some other companies also focus on building portfolios of tools for enhancing bioavailability. For example, Hovione offers 11 different ways to improve a compound’s solubility.

“The approach that we pick depends on the [active pharmaceutical ingredient’s] properties and also talks with the client about the doses that will be considered,” Winters says. “There’s really a continuum: Maybe a compound only needs a little assistance, so it doesn’t need expensive technology.”

Deciding what technology to use depends largely on teamwork. “We work very closely with the client,” Winters says, “and they are always welcome on-site.” Winters adds, “We also have a some secure Web-based information portals, and we upload data as we generate it in real time.”

Unlocking doors

For some compounds, effective bioavailability depends on getting inside cells. To help with this step in nucleotide-based drugs, Link Technologies (Bellshill, Scotland) provides customers with unique building blocks for synthesizing oligonucleotides. For example, Catherine McKeen, PhD, technical manager at Link Technologies, says, “Our products allow researchers to incorporate modifications into DNA or RNA that will help an oligonucleotide enter cells.” For instance, adding cholesterol can help an oligonucleotide achieve this. McKeen adds, “Some vitamins have also been shown to help an oligonucleotide enter cells.” Link Technologies makes these modified nucleic acids for proof-of-concept studies.

Protein- and peptide-based drugs face delivery and bioavailability challenges. “Peptides are not available orally, so they have to be injected,” says Henrik Rasmussen, MD, PhD, clinical affairs consultant to Unigene Laboratories (Boonton, N.J.) and president and CEO of Rasmussen Biotech & Pharma Consulting (Princeton, N.J.). For example, he says, “Everybody would prefer to replace the injected formulation of parathyroid hormone with an oral formulation.”

Digestive enzymes degrade peptides, and they are poorly absorbed through the intestinal cell layer. “To get peptide-based drugs to their targets, Unigene uses it’s Peptelligence oral-delivery technology,” says Nozer Mehta, PhD, chief scientific officer at Unigene. An enteric coating keeps the drug intact until it reaches the upper gastrointestinal tract. A water-soluble subcoat ensures that the drug and all of the excipients are released simultaneously. The released formulation includes a protease inhibitor to keep the drug intact and a permeation enhancer to deliver it across the lumen of the intestine.

Unigene’s Peptelligence oral-delivery technology protects a compound in the gastrointestinal tract, thereby getting the compound to its target. Source: Unigene

Unigene is testing this technology on an oral parathyroid hormone peptide, which recently demonstrated statistically significant efficacy in a Phase 2 clinical trial for the treatment of osteoporosis. “This is the only agent that builds bone to treat the effects of osteoporosis,” says Roxanne Tavakkol, vice president, global regulatory affairs and quality assurance at Unigene.

The MeltDose technology from Veloxis (Horsholm, Denmark) can also increase a compound’s bioavailability. As explained by the company’s executive vice president and chief commercial officer, John Weinberg, MD, “We take the API, melt it down to break up the particles and lattice networks. Then, we spray it through a proprietary nozzle onto carrier molecules. That formulation goes into a tablet.” The specific carrier molecule depends on the API.

This technology lies behind Veloxis’ LCP-Tacro, which is in late Phase 3 trials as a once-daily oral treatment for kidney- and liver-transplant patients. “The first Phase 3 was successful and a second is fully enrolled,” says Weinberg.

Extending half-life

Some proteins in the blood can be used to increase a compound’s bioavailability. For example, scientists at Novozymes Biopharma UK (Nottingham, U.K.) create variants of albumin that bind longer to this protein’s receptor. “By attaching the compound of interest to this modified albumin, the degree of half-life of this compound can be optimized to specific medical needs,” says Mark Perkins, PhD, customer solution manager at Novozymes Biopharma UK. 

For biological drugs, says Perkins, “short plasma half-lives … result in high dosing frequencies and reduced patient compliance, leading to increased healthcare costs.” He adds that the albumin-based technology “is designed to allow pharmaceutical companies to overcome these challenges by allowing the extension of drug half-life to the desired time, from days to weeks.”

The pharmaceutical companies using this technology, says Perkins, “include GlaxoSmithKline and TEVA Pharmaceuticals who already have Novozymes’ albumin technology-enabled protein drugs in pivotal Phase 3 clinical studies.”

Reengineering releaseVeloxis dissolves an active pharmaceutical ingredient into a meltable system of excipients, which is sprayed in a heated fashion through a specialized nozzle onto carrier particles. This so-called MeltDose technology can increase a compound’s bioavailability. Source: Veloxis

In some cases, just getting a compound to the right place, such as the tissue being targeted, could increase its bioavailability. As one approach to this, DSM Biomedical (Berkeley, Calif.) developed proprietary polyesteramides (PEAs). As Melissa Sherman—the company’s business director, drug delivery—explains, the PEAs “enhance bioavailability by providing better controlled drug-release kinetics through enzyme-mediated surface erosion, and polymer make-up that provides a more favorable, non-acidic environment for both the API and the surrounding tissue.” After the completion of the drug release, the body degrades the polymer. 

This technology is being tested in a range of active pharmaceutical ingredients aimed at many clinical conditions. As an example, Sherman says, “DSM’s PEA polymer was formulated into an innovative bioerodible coating, releasing the well-established sirolimus drug from a coronary drug-eluting stent developed by Svelte Medical Systems [New Providence, N.J.].”

With today’s range of technologies to enhance bioavailability, more drugs will reach tomorrow’s patients.

About the author
Mike May is a publishing consultant for science and technology based in Austin, Texas.