Alan Dove, PhD
What do suspicious-looking powders, false teeth, and magnets have in common? They’re all being developed as drug delivery systems.
For drug candidates, the first challenge is usually getting into the patient’s bloodstream. Injection is simple, but risky and inconvenient. Oral drugs avoid those problems, but must negotiate their way into the veins somehow. And pills are problematic if patients are unreliable or noncompliant, or if the dosing schedule is too complicated to remember.
Even with a reliable route to the bloodstream, the product won’t always end up in the right place. Drug transporter proteins may pump it into the wrong tissue entirely,
or the kidneys and liver may excrete it before it can do its job. For cancer therapies, the drug must also get into the tumor, which often has multiple mechanisms for excluding it.
The problem seems daunting, but researchers working on drug delivery are now addressing multiple aspects of it with surprising and innovative strategies. A survey of some of the more unusual drug delivery approaches hints at the depth and breadth of this impressive effort.
Dry bacillus, straight up
Some of the drawbacks of injected drugs and vaccines are clear to anyone who has taken a child to the pediatrician. While injections are a painful annoyance in the developed world, the problem is far worse in poor countries, where shortages of clean needles and trained medical staff sometimes make a shot more dangerous than the condition it treats.
To address that problem, the Bill and Melinda Gates Foundation, Seattle, Wash., offered a “challenge grant” for researchers to develop inhaled formulations of the most common childhood vaccines. “Our proposal was to develop an aerosolized form of BCG,” explains David Edwards, PhD, a professor in the Harvard School of Engineering and Applied Sciences and recipient of one of the Gates grants.
BCG (Bacillus Calmette-Guerin), made from a live, attenuated bovine tuberculosis bacterial strain, protects against a pediatric form of tuberculosis that is virtually nonexistent in the developed world. However, a BCG shot is standard in many poor countries, making it the most commonly administered childhood vaccine. “Many of the infants who are receiving BCG are receiving it in developing world environments, where injection poses a significant added risk,” says Edwards.
To make BCG, manufacturers currently freeze-dry the bacteria in a solution of salts and cryoprotectants, yielding a product that must be rehydrated and injected into the patient. Instead, Edwards and his colleagues decided to try spray-drying the microbe at room temperature, in a different buffer. “The ‘eureka’ was to remove the salt and cryoprotectants from the solution, which you would normally not think to do, but bacteria are so sturdy they can kind of handle it,” says Edwards.
The result was a viable, powdered preparation of BCG without cryoprotectants, ready to be inhaled. Because Tubercle Bacillus infects patients through the lungs, inhaled delivery might also have other benefits. The powder is quite stable at room temperature, so it might last longer in remote clinics without refrigeration.
Waiting to inhale
While vaccines need only stimulate an antibody response, which they may be able to do simply by replicating in the nasal and lung epithelia, drugs must actually reach the bloodstream.
Orally available compounds are often inhalable with little or no modification, as manufacturers of oxycodone are painfully aware. That’s why companies working on inhaled delivery focus mainly on reformulating drugs that are currently injected.
“We like unfair fights. We would never compete with an oral agent, we compete with injections,” says Steven Quay, PhD, president and CEO of Nastech Pharmaceutical Co. Inc., Bothell, Wash. The company currently makes an inhaled version of vitamin B12 for patients with anemia, but Quay concedes that it reaches a very small market. “We probably make a million [dollars] a year on it or less,” he says. Nastech’s pipeline is loaded for much bigger game, though, including inhaled formulations of parathyroid hormone for osteoporosis, peptide Y for obesity, and insulin for diabetes, all of which are now in clinical trials.
To make these large compounds inhalable, the company’s researchers try to force them through the nasal epithelium, a layer of cells inside the nose that are locked together like Roman soldiers’ shields. Two proteins, claudin and occludin, form the main clasps in the cells’ tight junctions, and Nastech has focused on developing peptides that can disrupt claudin-occludin binding temporarily.
“We put in something that interferes with the handshake that occurs between cells. Once the convection of the formulation occurs and the peptide gets degraded or diluted, the cells shake hands again,” says Quay.
In practice, the breakup and reunion appear to be a bit more complex than that, and the company has discovered that different drugs need different peptides or small molecules to help them through the junctions. “The hope was that one peptide would serve them all, but that hasn’t been the case,” says Quay, adding that “we try our varsity five or six compounds, and with any given drug one of them seems to be working.” The technique still can’t get really large proteins such as monoclonal antibodies through the epithelium, but it does appear to work with smaller proteins.
Inhaled formulations might also be able to clear another tough drug delivery hurdle: the blood-brain barrier. The barrier seems to be more permeable in the olfactory region than in other parts of the brain, raising the hope that inhaled psychiatric or neurologic drugs could take a shortcut into the central nervous system. Quay says Nastech is exploring that idea, but concedes that it remains controversial [F.W. Merkus and M.P. van den Berg, Drugs in R&D, vol. 8, no. 3, pp. 133-144 (2007)].
click to enlarge
Shown here is a schematic diagram of a potential nasal drug delivery system. (Source: Nastech Pharmaceutical Company Inc.)
The ultimate chewable tablet
Not everyone in the drug delivery field is counting on noses. For many drugs, the delivery problem is less about physiology than psychology: some patients simply have a hard time taking pills on a regular schedule. Psychiatric patients and recovering drug addicts are notoriously unreliable, but even the sharpest and most compliant patients sometimes have trouble if the dosing regimen is complicated. According to one recent survey, for example, some HIV patients take more than 60 pills daily, making drug dosing a full-time job [M.D. Furler et al., AIDS Patient Care STDS, vol. 4, pp. 245-257 (April 2006)].
If the IntelliDrug project succeeds, that job may soon be done by an ingenious automated system the size and shape of a tooth, which can be implanted directly in a patient’s jaw. It sounds like science fiction, but IntelliDrug is actually building on a proven platform.
In an unusual collaboration, electronic engineer Ben Beiski and dentist Andy Wolff, DDS, who are both staff scientists at Assuta Medical Centres in Israel, originally developed and tested the tooth package for electro-stimulation treatment of dry mouth. With some re-engineering, the pair adapted it to deliver medication rather than milliamps.
Installing a complex drug delivery system inside the mouth posed formidable technical hurdles. “There is a big challenge in avoiding clogging and avoiding contamination with the bacteria,” says Wolff, adding that “you also have the physical forces, mastication, tongue thrust, and so on, so you have to be strong, accurate, and also resistant against chemical attacks.”
The fake tooth holds an orally deliverable drug in powdered form, and uses sensors and pumps to deliver it on a preset schedule. “Water from saliva comes into the device and dissolves the drug, and then the drug is pushed by osmotic pressure outside the device,” Wolff explains. He adds that while the tooth package is ideal for long-term installation, the system could just as easily be put in a mouthguard-like structure that the patient could remove periodically.
Drugs with small molecular weights would be ideal for the tooth package, which has only a small reservoir to hold the medication. “For instance . . . naltrexone, which is a medicine used for drug addiction, has a very small molecular weight, and we calculated that the reservoir will be big enough to carry enough medication for about one to two months,” says Wolff. Larger molecules might require the mouthguard-style device and be limited to more compliant patients. The tooth-based system is scheduled to enter phase I clinical trials in a few months, delivering naltrexone to healthy volunteers to verify the system’s safety and reliability.
An attraction to chemotherapy
While oral and inhaled formulations are clearly easier to administer, some drugs will probably always have to be injected. For example, many new cancer therapies rely on liposomes to carry toxic compounds into tumors, reducing healthy tissues’ exposure to the drugs. One key to this approach is to use positively charged liposomes, which accumulate preferentially in tumor blood vessels.
Unfortunately, the charged liposomes can be unreliable, delivering plenty of drug to some tumors but little or none to others…until now. “We wanted to improve the distribution of these systems to target those areas, so we combined the electrostatic properties of the cationic liposomes with the strength of an externally applied magnetic field,” says Robert Campbell, PhD, assistant professor of pharmaceutical sciences at Northeastern University, Boston.
The concept behind Campbell’s system is deceptively simple: the researchers modified regular cationic liposomes to include small amounts of metal in addition to chemotherapy drugs. Administering these to mice with melanomas, the team then applied permanent magnets directly to the animals’ tumors, detaining the magnetic liposomes in the tumor tissue. “You can apply the magnet very easily to tumors that appear near the skin surface,” says Campbell, adding that “we could apply it to thyroid and breast as well.”
Once the magnetic liposomes arrive in the tumor blood vessels, they tend to stay there, rather than migrating deeper into the tumor tissue. However, Campbell and his colleagues have found that the tumor vasculature is actually more sensitive to chemotherapy drugs than the tumor tissue itself, so the treatment effectively kills off the tumor’s blood supply and starves the cancer cells [S. Dandamudi and R.B. Campbell, Acta Biochimica et Biophysica Sinica, vol. 1768, no. 3, pp. 427-438 (March 2007, Epub Oct. 21, 2006)].
Despite the system’s apparent simplicity, it requires some tinkering to work. “When you’re formulating these [liposomes], you have to give some thought to the optimal concentration of drug to magnetic material,” says Campbell. Indeed, the team has found that the metal can displace some of the drug in the liposomes, and Campbell says that the approach may not be suitable for all types of compounds.
It’s still unclear how well any of these new systems will work in humans, but there is little doubt that researchers are serious about solving the drug delivery problem. When it comes to showing up, the industry seems to be well on its way.
About the Author
Dove is a freelance writer based in New Haven, Conn.
This article was published in Drug Discovery & Development magazine: Vol. 10, No. 6, June, 2007, pp. 20-23.
Filed Under: Drug Discovery