Developments in Needle-Free Drug Delivery
New technologies and formulations enhance opportunities
By Paul Di Filippo
Sometime in the 23rd century, an ailing crewmember is rushed into the sickbay of the USS Enterprise, where crotchety but competent Dr. McCoy stands ready to treat him. A quick diagnosis via non-invasive tricorder, and the future physician knows just what treatment is needed. The required drug is administered swiftly and painlessly without ever breaking the patient's skin, thanks to McCoy's off-the-shelf "hypospray" gadget.
Exubera photo courtesy of Pfizer, Inc.
Such an easy, painless, needle-free injection might seem the stuff of purest science fiction, but the technology to administer drugs without use of the standard hypodermic syringe has been under development for at least 60 years. Could it be that the old-fashioned needle and syringe, first perfected more than 150 years ago, is on its way out at last?
The path to the needle's eventual extinction has not been an easy one. Infiltrating drugs past the body's defenses requires great ingenuity, not only in the creation of new devices and the exploitation of previously unused biological uptake pathways, but also in the tailoring of the molecules being delivered. Oftentimes, the perfect marriage of drug and device requires some finicky, clever match-making. The recent development of Exubera, the first inhalable insulin, and of its novel delivery device -- a collaboration by Pfizer, Nektar Therapeutics and The Tech Group -- is illustrative of the challenges faced by researchers in this area.
But before considering the exemplary story of Exubera as a parable of the quest to bypass the needle, let's take a look at what's happening elsewhere on this front.
The jet injector is perhaps the oldest device intended to eliminate the bluntly mechanical piercing of the skin by needles and syringes. Invented in the 1940's to facilitate mass innoculations of new soldiers, this device uses either a spring mechanism or pressurized gases--generally carbon dioxide or nitrogen, contained in small cartridge or large canister form--to force the aerosolized drug through the skin, either directly into the muscles or into the subcutaneous or intradermal layers. But older jet injectors exhibited several problems, such as possible contamination from one patient to another and awkwardness of use.
Now, however, the jet injector has undergone some recent improvements, thanks to such firms as Bioject, which has been working in this area since 1985. Bioject's streamlined and compact devices, such as the Biojector 2000, can deliver a large number of existing drugs without requiring them to be reformulated. In October of 2006, the Biojector 2000 was utilized with good results in trials for Fuzeon, an anti-HIV fusion inhibitor from Roche and Trimeris.
Bioject is not alone in realizing the utility of high-tech jet injectors, which offer an absence of dangerous accidental needle-sticks, and also increased attractiveness to patients leery of needles. In addition to the Biojector 2000, other options are Aradigm's IntraJect; BioValve's Miniject; the Medi-jector Vision from Antares; Crossject Medical Technology's Crossject; and PenJet Corporation's PenJet.
Certainly the nasal passages have long afforded a ready-made bodily ingress for drugs, ranging from over-the-counter decongestants to doctor-prescribed anti-allergy steroids like Flonase. Another well-known drug success story that involves the nasal route is Aviron's anti-influenza vaccine FluMist. First approved for sale in September 2003, FluMist sold 1.5 million doses in 2005. Becton, Dickinson and Co. provide the delivery device for FluMist, the BD Accuspray.
Perhaps encouraged by this success, researchers are, more and more, seeing the sensitive membranes of the human nose as a royal road to fast and effective needle-free delivery.
Nastech Pharmaceutical Co. identifies five advantages to administering drugs via nasal sprays:
• the ability to handle a large range of molecules;
• a non-invasive approach which fosters patient compliance;
• quick uptake;
• avoidance of metabolic degradation; and
• unequalled access to the brain, circumventing the infamously impenetrable blood-brain barrier.
• a non-invasive approach which fosters patient compliance;
• quick uptake;
• avoidance of metabolic degradation; and
• unequalled access to the brain, circumventing the infamously impenetrable blood-brain barrier.
Naturally, with such unique benefits to be achieved, Nastech has plunged ahead with nearly a dozen trials for nasally administered products that will be used to treat everything from obesity to osteoporosis to chronic pain, in partnership with such firms as P&G, Novo Nordisk and Amylin.
Perhaps one of the most intriguing potential products has been identified by a small start-up firm called Compellis Pharmaceuticals. The drug diltiazem, already prescribed to counteract high blood pressure, has been proven to suppress the appetite of rats when administered nasally. Compellis envisions a day when humans will whiff diltiazem prior to mealtimes and learn to moderate their caloric intake without suffering.
And if a firm called MedPharm has their way, the evening meal might eventually be followed by a nasal dose of somnolence-inducing benzodiazepine, for a good night's rest. Their partner in this venture? The charmingly named OptiNose, whose patented "bi-directional" technology claims to insure better delivery through the nostrils and avoidance of unwanted intake by the lungs.
Does size matter when it comes to needles? The average person, it seems safe to say, would immediately answer yes. Typically, injections in a hospital or office setting are accomplished by needles ranging from gauge 21 to 27, or 0.0320 to 0.0160 inches in diameter. Surely no human would relish a shot from a 10 gauge needle measuring a whopping 0.1340 inches in diameter. So perhaps, using this logic, a needle that was small enough would, paradoxically, no longer even be considered a needle. Any such device would, for all practical purposes, be "needle-free."
Such is the realm of microneedles. Smaller than a human hair, which measures on average 0.001 inches in diameter, microneedles penetrate the skin imperceptibly, delivering their multiple loads -- minuscule alone, but cumulatively effective--to the highly receptive intradermal, junctional or subcutaneous tissues.
BioValve, mentioned earlier for its Miniject technology, also offers microneedles in the form of Micro-Trans, their microneedle transdermal delivery system. Featuring an array of scores of microannula made of either metal or biodegradable polymers, these tiny patches not only deliver drugs but can also be configured to serve as sensors, determining fluid pressure and the like. BioValve's complementary e-Patch device serves as a reservoir for the microneedles. And 3M offers its Microstructured Transdermal System (MTS), which miraculously enough, in highly enlarged photographs, resembles not a matrix of microannula but rather a field of sharpened pyramids.
Surely one of the leaders in this area is Becton, Dickinson and Co. Formed more than a century ago, the company legendarily sold its first product in 1897: a glass syringe of all things, perhaps making its foray into microneedles appear predestined.
BD offers two microneedle devices, which it licenses to a wide variety of clients, including vaccine maker sanofi pasteur. The MicroInfusor is a disposable, wearable unit, while the Microinjection syringe is a handheld system.
But the path to perfecting microneedles was not an easy or simple one, involving much more than simply shrinking an already existing, well-known physical mechanism. Speaking with Philip Green, the Director of Alternative Drug Delivery at BD Medical Pharmaceutical Systems, reveals the extent of the challenges involved. Developing the technology, Dr. Green reveals, was "a bit more complex than anyone really imagined. When you put substances into that part of the skin, there's a lot of issues about making sure that the injection is reliable and the drug doesn't leak everywhere."
After overcoming these obstacles, BD also had to focus on eventually making microneedles safe and easily comprehendable for healthcare professionals and possibly for self-administration by patients outside a clinical setting. "Our initial focus is really on professional use, but we are beginning to think about how these devices can be put in the hands of anybody. That's a quite challenging step," says Dr. Green.
Yet another factor in the perfection of BD microneedle technology involved working hand-in-hand with the drug makers to tailor or select their most appropriate molecules for this method of delivery. (A theme that will resurface in the Exubera story.) "Putting drugs into that [intradermal] layer of skin may offer faster uptake and offset. Some of the larger, protein-like drugs seem to be more rapidly and more completely absorbed when given intradermally rather than subcutaneously. But that's a two-edged sword. We do have to work closely with pharma companies. If you change the pharmacokinetics, then it becomes potentially a new drug," Dr. Green warns.
Looking to the future, he states that the company hopes its product will someday help cancer patients: "We have a big focus on trying to improve delivery of drugs for cancer." Drugs delivered by microneedles will often preferentially migrate to the lymphatic system, and this could potentially help in the treatment of certain types of cancer, including certain types of leukemia, lymphomas, melanomas, head and neck cancers, etc. Additionally, the new field of therapeutic cancer vaccines that stimulate the immune system itself to destroy cancer cells occupies Dr. Green's attention: "There are about 60 or 70 companies out there focusing on developing cancer vaccines. One called Dendreon probably has a chance to be the first to launch a product, against prostate cancer."
Concluding, he affirms, "We're a company that's always looking for new technologies. There's a few frontiers left, and when you're a company that has a big interest in needles and syringes and people are trying to come up with alternatives to that, the best way of responding is to get involved yourself."
One radical method of delivering molecules to the body without continually piercing the skin with needles is to penetrate the skin only once, through a surgical procedure, and implant a source of drugs directly into the body.
Autonomous pumps and reservoirs are one method of achieving this end, and several companies provide them. Medtronic currently offers the only programmable unit that delivers drugs intrathecally directly to the spinal fluid. But at least half a dozen other companies manufacture implantable insulin-delivery systems.
However, implants need not be complicated, sizable units with external power sources and several moving parts. Wyeth Pharmaceutical's famous contraceptive, Norplant, although no longer marketed in the U.S., still stands out in public perception as a prominent non-mechanical drug delivery implant.
At one company, DURECT, where the goal is "to deliver the right drug to the right site in the right amount at the right time," they have been focused -- in addition to transdermal patches and sustained-release oral gel-caps -- on this type of smaller implant, some of them powered by the body's own process of osmosis.
Dr. Felix Theeuwes is chairman, co-founder, and chief scientific officer at DURECT Corp., established in July of 1998 as a spinoff from ALZA Corp., where Dr. Theeuwes worked from 1970 to 1999. (Founded in 1968 by Dr. Alejandro (Alex) Zaffaroni, ALZA is arguably the first pioneer in the modernization of drug delivery systems, and figures prominently, along with Dr. Theeuwes, in another needle-free process I'll cover in the next section.)
Dr. Theeuwes is particularly pleased with his firm's Chronogesic Pain Therapy System, which employs the DUROS™ implant technology, "a small titanium pump, about the size of a match stick, which is implanted under the skin of a patient in a simple out-patient procedure," according to the company. "Long-acting implantables," maintains Dr. Theeuwes, "have something significant to offer to society, to the patient, and to the biotech industry, and that's why we've focused on making a contribution in this area." DUROS™, says Dr. Theeuwes, "has one moving part, a piston that delivers an active agent at a dependably constant rate for long durations by osmosis."
Perhaps even more revolutionary is the SABER™ technology, in which the chosen drug is suspended in a viscous, semi-solid gel substrate that degrades in a controlled-release fashion over time: days, weeks or months. This mass is positioned in the body during allied surgical procedures and functions, says Dr. Theeuwes, "almost like an artificial gland. You don't have to worry about it for the course of treatment."
Finally, although transdermal patches are a relatively old drug-delivery technology, these too offer room for improvement and continued applicability. DURECT's TRANSDUR™-Sufentanil patch is one-fifth the size of conventional patches but lasts longer than its competitors, according to the company.
Dr. Theeuwes believes that DURECT's ultimate strengths lie in its abilities to get new drugs to market faster and more economically. "We can potentially create a blockbuster drug in about half the time and for a tenth of the cost that the pharmaceutical industry can when developing a new chemical entity. And that's a great benefit to society and the patient."
The iontophoretic effect is a natural process recognized in general since the time of Michael Faraday (1791-1867) that takes advantage of the electrical charge inherent in certain biologically active molecules. By applying a small electrical current to the drug and to the patient's skin, the drug is transported directly through the epidermis by a variety of cellular channels.
Although this effect has been known for some time, harnessing it to a practical device took some doing. One of the early pioneers in this field was the firm Iomed, which today offers a variety of products utilizing the process.
A newer device ingeniously employing reverse iontophoresis has achieved some renown of late. Worn on the wrist by those suffering from diabetes, the GlucoWatch draws out small quantities of interstitial cellular fluid and tests it at 20-minute intervals for glucose levels.
But refining the iontophoresis process to drive molecules even more efficiently into the body has long been a motivating force at the firm named ALZA. One expert I spoke with likens the difficult task of getting macromolecules or proteins through the epidermis to "trying to shove a basketball through a chainlink fence.")
In 1987, when he was still employed at ALZA (which was purchased in 2001 by Johnson & Johnson for $11 billion, the company's largest acquisition at the time), Dr. Theeuwes began a project into this "active transport" method. And now, after his departure from ALZA, the Ionsys device -- employing the proprietary E-TRANS technology and marketed by another J&J subsidiary, Ortho-McNeil--is ready to be utilized for "the short-term management of acute post-operative pain in adult patients requiring opioid analgesia during hospitalization," serving as "the first needle-free, patient-activated analgesic system."
Initially at least, Ionsys, which delivers the opiate fentanyl in accordance with the self-determined needs of the patient, is being restricted to hospital and clinical settings. But even so, patients employing the compact Ionsys unit will find their lives immensely improved, as they are released from traditional IV tethers and bulky devices.
Greg Panico, senior director at the CNS/Internal Medicine Communications division of Johnson & Johnson, has nothing but praise for the team that developed Ionsys during a decade. "The team worked hard to bring the project through the development and approval process." And Mr. Panico foresees a bright future for Ionsys: "Any charged drugs that would otherwise be delivered by an injection or an intravenous infusion pump may be good candidates for E-TRANS delivery."
The pulmonary route for providing medicines is surely recognized by nearly everyone today, lay person and professional alike. The rising tide of asthma ensures that nearly every person knows someone who relies on a Metered Dose Inhaler (MDI) for relief from their symptoms. However, a drug that is inhaled does not necessarily have to be targeted at an ailment that is specific to the lungs. The immense active surface area of the lungs provides a handy uptake mechanism for drugs aimed at non-local or systemic ailments as well.
But for delivering this new class of drugs to the lungs, the common MDI does not always suffice. A new generation of devices is emerging from the labs. And this new breed of delivery mechanism often relies and insists on having freshly co-evolved drug formulations for maximum ease and efficiency of delivery and uptake.
Few people know the necessity for new pulmonary drug formulations better than Larry Brown, chief technology officer and vice president at Epic Therapeutics, a wholly- owned subsidiary of Baxter Healthcare Corporation. Brown has been instrumental in perfecting a formulation process called PROMAXX technology, under development since 2002. "This unique technology," explains Brown, "allows us to take proteins and other biotechnology-based drugs and form them into uniform-sized microspheres. Unlike other technologies in the drug-delivery world that generally formulate microspheres using some biodegradable polymers, we actually make the microsphere out of the protein itself." This yields an essentially excipient-free microsphere.
Avoiding the use of excipients provides several medical advantages for pulmonary administration. "You deliver far less mass to the lungs without the addition of potentially irritating ingredients," Brown remarks. "And we're able to make these microspheres precisely in the particle-size range that you would predict would reach the deep lungs." Only a small percentage -- less than 0.2% -- of polyethelyne glycol remains in the microspheres after the formulation process. Despite the lack of excipients, PROMAXX protein microspheres are exceptionally stable, said Dr. Brown.
Epic is also investigating different cutting-edge dry powder inhalers for future use, when perhaps human-growth hormones, alpha-1 antitrypsin (a treatment for emphysema), and nucleic acids such as siRNA (short interfering RNA) and antisense oligonucleotides will be formed into microspheres and find their way into the body through the lungs.
Other firms are also developing new pulmonary devices and formulations. Alkermes offers its AIR system and Aradigm sells its AERx product, but certainly no recent product has gotten more attention than Exubera, the first inhalable insulin to reach the market. Exubera, which is being marketed by Pfizer, was created by Nektar Therapeutics. And its unprecedented delivery system reached reality via the manufacturing expertise of The Tech Group. The story of how drug and device evolved together illustrates how needle-free drug delivery is often a two-pronged path.
John S. Patton, co-founder and chief scientific officer of Nektar, has devoted 20 years of his career to this project, starting at Genentech in 1986. After first working with human-growth hormones, he and his team switched to insulin as their focus for a drug that would benefit from pulmonary delivery. They considered liquid forms of the protein, but eventually decided to attempt to perfect a dry powder form, thus creating the world's first room-temperature-stable insulin. The powder form -- employing excipients such as citrates and glycine -- also allows for more "drug per puff."
This unprecedented bio-material required new manufacturing techniques, says Mr. Patton. "My partner, Bob Platz, brought one of the coolest innovations to this field with spray-drying. These small powders had been made by jet-milling, a high-energy, rather crude process that can actually change the solid state of the material and give you a mixture of crystals and amorphous powders, often electrostatically charged. What Bob came up with was a process that's been used in the food industry for a while, that of spray-drying. But the particles that they make in the food industry were very large particle sizes, hundreds of microns. We were trying to make particles that were one micron, two microns. So Bob and the engineers had to make all sorts of unique modifications. They also developed a cyclone process that would spin the powder and allow it to be collected."
Finally, a team led by Jim Parks "figured out a brand-new, very elegant way to get these very fine powders in reproducible, reliable amounts into blister-packs."
This immense task accomplished, all that lay ahead was the not insignificant job of devising a mechanism to deliver Exubera precisely and reliably, under all conditions of humidity and temperature, in a way that would be self-evident and helpful to the user.
"At first we were just carrying around blocks of plastic carved to look like a real device," recalls Mr. Patton. But once the powder and its properties were finalized, work on the actual device began. The resulting futuristic-looking unit, about the size of an eyeglass case when not telescoped for use, had to disagglomerate a dose's worth of particles, suspend them in a transparent chamber as an aerosol cloud so the patient could see the charge was ready, and then administer it at a slow, comfortable rate. After much effort, team leader Adrian Smith succeeded in producing this dramatically new inhaler.
Finally, to churn out the radical new inhaler in large quantities, Nektar turned to the expertise of the Tech Group, one of the world's leading manufacturers of pharmaceutical delivery systems.
Mike Treadaway, manager of the Drug Delivery Devices Division for The Tech Group, recalls how the demands of producing the new unit necessitated starting completely from scratch. "We had a facility within the Tech Group [in Tempe, AZ] that we gutted and built specifically to support this project. The assembly consists of three sub-assemblies. One is fully automated, one is semi-automated, and one is manual. We had to get those all developed and validated. This device has to be manufactured under pharma standards. We were inspected by two representatives from the FDA -- just as if we were manufacturing a drug."
Mr. Treadaway expects that the new techniques mastered during the manufacture of the Exubera device, such as two-shot molding technology, will feed back into future products as well.
And the ultimate reward for all this hard work and creativity? Andrew Forman, an analyst for WR Hambrecht & Co., estimates that annual sales of Exubera will reach $2.8 billion by 2010.
Dr. McCoy's hyposprays might not be available at your local pharmacy just yet. But the ingenuity and drive of current researchers and manufacturers guarantee that such idealized needle-free methods are just around the corner.