3M, Catalent, And MannKind Work On Withdrawing The Needle

A single hypodermic needle has been the key apparatus for injecting substances into the bloodstream since 1657. That was when the English architect and scientist Sir Christopher Wren first fashioned a goose quill needle and animal bladder syringe to perform intravenous injections on dogs.

Despite decades of research, the syringe and needle continue to be the primary option for ensuring that large-molecule drugs are delivered intact to the blood. Most large-molecule drugs, if consumed orally, would break down in the gastrointestinal tract.

But administering a drug hypodermically has its drawbacks. The needle can be painful, particularly for patients such as diabetics, who require regular doses of human insulin. And in some cases, hypodermic needles keep patients from being able to self-administer medicine.

Scores of companies over the past 40 years have failed in efforts to make large molecules orally bioavailable. For some drugs currently injected by needle, though, alternative delivery systems are starting to emerge. Among the potential alternatives are under-the-tongue tablets, microneedle patches, inhalation powders, and ointments that enter the body via hair follicles. Each system requires an innovative approach to drug formulation.

Benefits for drug companies could include intellectual property protection and a route to new markets. The business potential for needle-free delivery systems is huge, with analysts estimating current large-molecule drug sales of $110 billion per year in the U.S. alone.

The systems could have patient benefits as well, including more effective disease management. Yet some technology developers say they are having a tough time convincing drug companies that their technologies are worth the commercial risk.

One such developer is the pharmaceutical services firm Catalent, which is pioneering tablets that are placed under the tongue to deliver large-molecule drugs to the blood. The tablets feature undisclosed adjuvants and other ingredients that enhance the bioavailability of the active molecule. They are made using Catalent’s Zydis fast-dissolve freeze-dried production process, which enables them to be dispersed in the mouth in as little as five seconds without water.

The drug molecules penetrate through biological membranes under the tongue via a process named passive diffusion, which is largely dependent on the physicochemical properties of a drug. The drug molecules can either diffuse through junctions between cells or through cell membranes.

Catalent was one of a handful of firms highlighting drug delivery approaches at a meeting held recently near London by the Applied Drug Delivery Institute, an organization that Catalent set up in June 2012 to promote alternative drug delivery.

To enhance the body’s uptake of large molecules in tablet form, Catalent has been testing nanoparticles generated by wet milling, Robert J. Smith, R&D director for Zydis, told attendees at the London meeting. The formulation has to be modified to suit each individual drug, he said.

The firm has been applying its technology to vaccines that otherwise would have to be injected. “We’ve been doing a lot of work around influenza vaccines,” Smith said. In trials, Catalent has demonstrated that delivery of a flu vaccine via its tablet system leads to improved immunity in mice.

The firm tests its product by placing tiny tablets under the tongues of mice. “This is an art in itself,” Smith said.

Catalent is also part of a consortium that has been awarded funding from the European Commission’s Horizon 2020 research program to develop an oral delivery system for an undisclosed injectable HIV drug. The firm hopes to begin bench-scale formulation trials within the next three months “to identify what we need” to deliver the drug, Smith said.

The successful development of tablets for delivering large-molecule drugs such as vaccines and HIV treatments would have multiple benefits, particularly in developing countries, Smith said. A big one would be the replacement of so-called cold-chain supply systems for vials of injectable liquid vaccines, which currently have to be chilled until they are administered. In contrast, Catalent says its tablet technology features a coating that could allow vaccines to be kept at room temperature for up to four years.

Rather than tablets, 3M is developing microneedle patches that are applied to the skin. Based on both hollow and solid needles, the patches come with companion handheld devices so patients can apply them at home. “You can hardly feel them,” Mark Tomai, an immunologist who is head of microneedle business development for 3M, told the audience at the London meeting.

The hollow-microneedle system features 12 needles of up to 1,500 µm in length. They create microchannels in the skin that can together deliver up to 2 mL of vaccine, large-molecule protein, or small-molecule drug. The drug takes from 15 seconds to 15 minutes to administer depending on volume and formulation.

“We’ve worked very hard on reducing that delivery time. It’s a trade-off between pain and time,” said Kirsty Gapp, head of 3M’s microneedle technology.

The solid-microneedle system is molded from durable medical-grade polymer. The needles, which are up to 700 µm in length, can together deliver 300 µg of a drug.

3M applies the active pharmaceutical ingredient to the solid needles with a precision coating system, which means that precisely the right dose is coated onto the microneedles, Gapp said.

Even the shorter solid microneedles penetrate the dermis, where the drug may then be introduced to the bloodstream via lymphatic capillaries. Potential benefits include faster absorption and higher bioavailability of some drugs compared with hypodermic needle delivery, according to Gapp.

The limitation of the solid-needle system, however, is that 300 µg is an insufficient volume for many drugs. 3M is still awaiting its first commercial applications for both the hollow and solid systems. “We are still some way before we have a commercial product on the market,” Gapp acknowledged.

Whereas 3M is still seeking its first pharma customer, in February the California-based biotech firm MannKind launched Afrezza, a human insulin that is administered not as an injected liquid but as an inhaled powder.

MannKind and its marketing partner, Sanofi, chose to pursue such a strategy despite major failures in recent years to introduce inhalable insulin. Most notable is Pfizer’s 2007 withdrawal of its Exubera insulin one year after launch because of poor patient uptake and safety concerns. It was a move that cost the drug giant $2.8 billion.

Although Afrezza marks a step forward, Sanofi and MannKind acknowledge that it is “not a substitute for long-acting insulin” and must be used in combination with injections. Because of the delivery method, it is also not recommended for smokers or diabetics with asthma or lung conditions.

Patient adoption of the drug has been slow. MannKind blames precautionary laws that require patients to qualify as suitable for the drug. “On the basis of early patient feedback, we remain supremely confident this will be a blockbuster product,” MannKind’s chief financial officer, Matthew J. Pfeffer, tells C&EN.

Pfeffer’s claim is backed by some positive comments about Afrezza across social media. On Twitter, for example, Howard Stevenson (@Afrezzaguy), a type 1 diabetic who started taking Afrezza in April and says he has no connection to MannKind, recently wrote, “What else do I say? Life-changing. Miracle drug. Awesome control. Long healthy life. Cheers to MannKind Corp.” He also tweeted, “I don’t know what to do with all my spare time since I don’t have to fight spikes and hypos anymore.”

Other major pharma companies are considering even more creative ways of delivering large molecules needle-free. Swiss drugmaker Novartis says it is collaborating with the Google Ventures-backed start-up Rani Therapeutics to deliver biotech drugs via a “robotic pill.”

Coated with a soluble polymer, Rani’s pill is swallowed like a traditional pill. When it reaches the intestine, acids dissolve both the polymer and a valve separating compartments filled with citric acid and sodium bicarbonate.

The chemicals mix to form carbon dioxide, which inflates a balloon and pushes tiny needles made of sugar into the intestinal wall. The needles detach to deliver their drug payload. The remaining pill components pass through the body. The pill is designed to deliver large molecules, including peptides, proteins, and antibodies.

Rani plans to run feasibility tests in the next 18 to 24 months to evaluate how certain Novartis biologic drugs can be delivered to the bloodstream without needles.

Further in the future, single-needle injections could be replaced by topical ointments that can be absorbed through hair follicles. Still at the lab phase, the approach is being pursued by Claus-Michael Lehr, a professor of drug delivery at Saarland University, in Germany.

Lehr has been developing ointments featuring nanomaterials in a hydroxyethyl cellulose gel that is applied to the forearm. When the skin is massaged, the drug enters the body via tiny spaces between hair and the hair follicle. Massaging causes the follicle to act like “a natural pump” that draws the ointment into the body, Lehr said at the London meeting.

The concept has already been proven in studies with mice and with pigs’ ears, said Lehr, who is also joint chief executive of PharmBioTec, a company started by Saarland to commercialize drug delivery technologies. Initial studies show that 5% of the dose enters the skin. “Perhaps this is sufficient,” he said. The initial research was funded by the Bill & Melinda Gates Foundation.

Other delivery techniques are also attracting attention. Intranasal and pulmonary routes have good potential for large-molecule drugs because the absorption membranes are relatively permeable and drugs are able to enter the body intact, according to Catalent’s drug delivery institute. Two marketed peptide drugs are already delivered by these routes.

But despite such successes, alternative drug delivery technologies have yet to be widely accepted by the risk-averse pharmaceutical industry, according to Ralph Lipp, head of Indianapolis-based Lipp Life Sciences. “Already only one in 10 drugs in development makes it to the market. Add another delivery technology, and you can subtract another 2% of probability,” he said at the London meeting.

That’s partly because the Food & Drug Administration is reluctant to approve drugs deploying novel delivery systems. “Regulators first want to see a drug using standard delivery technology, then look at novel delivery technologies,” 3M’s Tomai said.

Another reason for the slow uptake is that the handful of companies in control of the vaccines market is not interested in overhauling the way products are administered, Catalent’s Smith said. “Their processes could become redundant if Catalent’s oral approach really takes off,” he pointed out.

Still, wider market forces suggest that alternative drug delivery systems will be adopted. In 2014, large molecules made up one-quarter of new drugs approved by FDA. In the competitive generics market, meanwhile, pharmaceutical companies increasingly need to differentiate their products.

Ultimately, though, it will come down to patients. If alternative drug delivery systems sufficiently improve patients’ quality of life at a reasonable cost, then traditional hypodermic needles really could be consigned to the history books.