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Biotechnol Healthc. 2007 December; 4(6): 15–16.
PMCID: PMC2651724

Ousting the “Ouch Factor” in Drug Delivery

People just don’t like needles. But needles are what they’ll almost certainly get if they are candidates for a biologic therapy, as most are administered by intravenous infusion or subcutaneous injection.

Eliminating the “ouch” makes for a monster market opportunity, especially as more and more macromolecule biologics come to market. But it’s not just fear of needles that drives the search for new drug-delivery technologies. Infusion is inconvenient, time consuming, labor intensive, and costly; self-administered injection with a syringe depends on proper technique, accurate dosing, and is inconvenient at best. Ultimately, all of these factors adversely affect a patient’s adherence to therapy.

The most promising alternatives to infusion and syringe injection of biologic drugs appear to be pulmonary, “needle-free,” pen injection, and oral delivery methods. Other drug delivery technologies, such as depot injection and implants, still rely on needle injection or surgical implantation, but greatly reduce injection frequency (as with injectable extended-release technologies) or eliminate injection entirely (in the case of implants).


It was big news, but it wasn’t good news. Just 11 months after Exubera (insulin [rDNA origin]) inhalation powder for both type 1 and 2 diabetes was launched, Pfizer announced in October that it would no longer manufacture or market the product. CEO Jeffrey Kindler said Exubera failed to gain acceptance among patients and physicians, due in part to its rather sizeable and complex inhalation contraption, potential difficulties with dosing, and existing insulin delivery technologies already on the market, including needle-free and pen injectors.

However, Exubera’s demise won’t stop the pulmonary drug-delivery train. Or so says George Perros, a medical technology consultant with Greystone Associates, in Amherst, N.H.

“Pulmonary drug delivery of proteins and peptides should be a major factor in five years,” he says. “Exubera proved the concept could work, and its withdrawal was due to unmet business goals. For chronic ailments, you’re looking for safety and user-friendliness, and that’s where inhalation can have a distinct advantage over injection.”


Also referred to as jet injection, needle-free drug delivery consistently delivers injections to the same depth as by syringe, equals or exceeds the bioavailability of the drug, does not require reformulation of liquid medications, and eliminates the danger of accidental needle sticks.

Pressure to propel the stream of liquid medication is provided either by a spring or by a cartridge of compressed CO2 gas, and can be calibrated to deliver specific medication volumes by intra-dermal, subcutaneous, or intramuscular means. However, some studies suggest that erythema, hematoma, bleeding, and pain at the injection site are similar to or greater than that experienced with needles.

According to Perros, needle-free injection is used primarily in administering insulin, human growth hormone, and, to a lesser degree, vaccines.

“Needle-free injection does have a place in protein delivery, but has struggled to move beyond niche markets,” says Perros. “The emerging generation of needle-free injectors are similar to devices that pen injector manufacturers have developed. These new devices tend to be prefilled disposable designs or reusable devices that utilize a cartridge system.”


Used mainly for frequent self-injection of insulin, along with hormones and other medications, pen injectors are available with a dazzling variety of features.

“Pen injectors tend to be designed specifically for a company and a particular therapy, and a lot of it has to do with aesthetics and branding in an age when direct-to-consumer marketing is such a big deal,” says Perros. Auto-injectors are spring-powered, but automatically insert the needle and perform the injection.

“Pen injectors are more costly to develop than a disposable syringe, but they’re relatively safe and user friendly, and that translates to improved compliance,” Perros comments. “Many new protein and peptide drugs target chronic ailments, and if you’ve got a drug that costs $50, $100, or $500 a dose, it’s sensible to have a device that’s going to be used properly, that’s going to be used, period, and that’s where pen injection devices are finding a home.”


Speaking of compliance, Lewis H. Bender, MS, MBA, chief technology officer at Emisphere Technologies, in Tarrytown, N.Y., notes that compliance is significantly higher with oral rather than parenteral delivery technologies, especially injectables for medications that treat chronic conditions.

Bender may be right about that, but everyone knows proteins and peptides can’t survive through the human gastrointestinal tract.

Or can they?

“With our eligen technology, we’re able to achieve therapeutic blood levels of proteins when given orally,” Bender claims. “You see absolutely no absorption.”

Emisphere’s eligen technology is based on the use of proprietary, synthetic chemical compounds known as delivery agents or “carriers,” that enable the transport of therapeutic macromolecules across biological membranes, such as those of the GI tract, without altering the chemical form or biological integrity of the therapeutic molecule, or affecting the integrity of cell membranes or cyto-skeletal structures. The medications can be formulated as solutions, tablets, or capsules.

“We all know how to swallow a tablet or a capsule,” says Bender. “It’s the ultimate in convenience.”

Emisphere has customized approximately 4,000 carriers for a variety of therapeutic agents. These carriers vary in chemical structure, solubility, hydrophobicity, electrostatic, and other properties.

Because of predictable degradation, oral delivery requires larger doses — 5 to 20 times higher — to attain therapeutic blood levels equivalent to those achieved with infusion or injection. But typical e-coli-derived macromolecule production costs can amount to pennies per milligram, says Bender.

“You’re talking microgram quantities, and the manufacturing cost at scale can be as low as a few pennies per tablet. When you include the cost of an injectable device and its disposal, oral could be less expensive than injectable.”

“Managed care would love to see every drug in oral form. It’s safe and cheap, and shelf life shouldn’t be an issue,” says Perros. “Oral is sort of the Holy Grail.”


What if you still had to inject your biotech medication, but not as often?

Durect Corp., in Cupertino, Calif., may provide an alternative with its sustained-release Saber delivery system, which can deliver protein and peptide drugs for as long as three months from a single injection. A diluent that is added before injection diffuses, leaving a biodegradable gel depot that can be formulated to deliver a drug systemically or target a specific site over 1 to 90 days.

Durect’s Durin biodegradable implants, which can be made in a variety of shapes, are another technology that is used for sustained-release delivery of small- and large-molecule drugs.


The number of companies working on drug delivery systems, the potential rewards for a breakthrough method, and the prolific pipeline of new macromolecule therapeutics coming to market all suggest continued robust growth in drug delivery technologies, perhaps based on unforeseen, exotic discoveries. Some examples:

  • Recent research with a “peptide chaperon” may provide a way to deliver macromolecule drugs via transdermal patches
  • Irish researchers have developed a technique that uses light to initiate a photochemical reaction, which in turn releases a drug already delivered to a site in the body, such as diseased tissue, as long as the light continues to shine
  • Implantable microelectronic machines can be programmed to release drugs from a reservoir

And then there’s the intrigue of nanotechnology.

“When you talk about sustained, controlled, and even oral delivery methods, a number of companies are working with nanotech as a way to encapsulate a protein while it goes through the upper digestive system. Once it reaches the small intestine, it gets absorbed into the bloodstream and produces the intended physiological effect,” says Perros. “It’s an elegant way to address the problem of oral protein delivery, but it’s questionable whether this approach can be developed to work on a wide scale without customization for each drug.”

Articles from Biotechnology Healthcare are provided here courtesy of MediMedia, USA