Following the difficulties of drug development, researchers must find the best method for delivering designated dosages in a reliable manner
Canavan is a freelance
writer based in New York
After the difficult work and expense of getting a drug through preclinical trials, the hard work is done, right? Wrong. At this stage, a new set of challenges emerge surrounding optimal drug formulation. Intravenous delivery may seem a logical choice, but patients hate it. Oral delivery is painless, but it delays the drug’s activity. There are a number of other formulations that researchers have experimented with that have various advantages. Pulmonary delivery is one of them.
“The lung is naturally permeable to many peptides and proteins, and very permeable to small molecules,” says John Patton, co-founder and chief scientific officer of
Nektar Therapeutics, San Carlos, Calif. “Besides injecting, there’s no way to get a drug into your body faster or cleaner than inhalation.” When considering diseases of the lung, the rationale for using pulmonary administration is obvious, but it makes sense for systemic therapies as well. “Inhalation is very compelling because you can lower the body burden of drug to 1% or 2% of what you’d have to take if you took a pill.”
If pulmonary delivery is the route to be taken, here are the obstacles to getting there:
• Bioavailability: “It turns out that insulin has a bioavailability in the lung of about 30% to 40%, but when you consider the losses in the delivery device and in the throat, it comes out to be around 10%,” says Patton. So bioavailability is clearly a factor when considering dose.
• Dose: Measuring a delivered pulmonary dose in an animal can be done directly, but invasively. It’s a bit trickier with humans. (See “Good Drug Gone Bad,” page 28.)
• Reliability: “Metered-dose inhalers are notoriously imprecise. People get all kinds of doses,” says Patton. “Our new insulin delivery device is as accurate as injections, if not more so.” Yet the device is utterly dependent on the formulation’s dispersability.
• Dispersability: “It’s relatively easy to make a 1- or 2-µm particle, but getting that particle to disperse gently into an air stream, and not as a bunch of clumps” is more problematic, says Patton. If the drug naturally clumps, then the choice of excipient can make or break a product. “If you’ve got a poorly dispersible drug, you can totally rescue it if you use the right excipient.” But, Patton warns, be careful what you choose: novel excipients can be as hard to get approved as novel drugs.
Tracking drug delivery
It is often the case that the dose intended may not be the dose received. For inhaled products, loss can occur in the device, on the tongue, or down the throat. To know
how much of the drug made it to the target, it helps to be able to track the compound once it has been administered. Gamma scintigraphy can determine where a drug is, beginning the moment it entered the body, says Erik Sandefer, PhD, co-founder of Scintipharma Inc., Lexington, Ky.
This is accomplished by including a gamma emitter in the drug’s formulation; however, the emitter is not bonded to the active compound, but rather to a surrogate marker. “So, we’re always looking at the marker, and if you formulated it properly, it’s mimicking the release pattern of the drug itself,” says Sandefer. This technique can be used to track drugs from nearly any point of entry, be it nose, eye, or the southern outpost of the alimentary canal, but Sandefer works mostly with pills. Swallow a pill and he can tell and show where it is and when.
“It’s not like an MRI or a CAT scan where you have this beautiful anatomical image with all the various reference points,” says Sandefer. But it’s picture perfect to him. “The beauty of using gamma scintigraphy is it’s also quantifiable. You can determine the percentage of radioactive material in the stomach, in the early intestine, in the distal intestine . . . And from that you can generate a dynamic gastrointestinal transit curve.” The bottom line is that Sandefer can tell where and when drugs are absorbed, and if absorption is a problem, he can advise how the formulation should be changed.
A matter of taste
Many tests indicate how a drug is taken up, but few can determine how well it went down. And since taste is, well, a matter of taste, it’s best to leave this determination to
|Good Drug Gone Bad
The purpose of a drug reformulation is often to facilitate its use—but not always. Sometimes a drug is too good. Take, for example, the sustained-release, opioid-derived Oxycontin (oxycodone). “Opioids have a near-perfect binding affinity with the so-called ‘feel-good’ chemicals in the brain. That’s the good news. The bad news is that drug abusers have discovered that you can very easily turn a sustained-release drug into an immediate-release drug by crushing it. It’s as easy as crushing an M&M,” says Remi Barbier, president and CEO of Pain Therapeutics Inc., South San Francisco, Calif.
This bit of delinquent ingenuity has had disastrous consequences. Deaths from Oxycontin abuse run in the hundreds annually, and reports of related cases in the emergency room are in the thousands. It has also become a significant law-enforcement problem. “Call any pharmacist,” says Barbier, “and ask them how many times they’ve been robbed for Oxycontin. Not even for cash—they leave that—they just want the Oxycontin.”
The challenge of reformulation first required an understanding of the abuser’s methods. “We mapped out all the simple ways of abusing Oxycontin, and that includes crushing, freezing, heating, microwaving, dissolving in a weak acid or base—all the obvious things.” With these parameters in mind, Pain Therapeutics designed Remoxy. “Think of a Buckyball [a buckminsterfullerene]. When you insert a chemical in the ball and then start hammering away at it, it won’t come out. We’ve essentially encapsulated each molecule of oxycodone around some very tenacious molecules that simply will not let it go.” At least, not until they’re ready—that is, only under physiologic conditions.
The resulting product is a squishy gel capsule. “Inside, it’s like salt water taffy on a hot day—very sticky.” You can’t smoke it, shoot it, or snort it, and, according to Barbier, it tastes incredibly unpleasant, although he admits that’s a low hurdle for abusers. He is also quick to point out its limitations. “Remoxy is not abuse-proof. Nothing is. Remoxy is tamper resistant. What we are trying to do is raise the bar so high that the average user will migrate away from oxycodone and toward some other drug of choice.” The impending success of this effort (Remoxy is in phase III development) is not merely of interest to the drug industry. The Drug Enforcement Agency has also taken notice, and Barbier has been invited to Washington to present his findings.
a device, a machine that can be calibrated—the Astree Electronic Tongue. “The e-tongue is mainly used by oral formulation developers—from simple syrups or emulsions down to wafers, soft gel caps, chewing gums, effervescents, and so on,” says Jean-Christophe Mifsud, PhD, cofounder of Alpha M.O.S., Toulouse, France, makers of the Electronic Tongue.
The e-tongue works by comparing readings from a given sample to a data set generated by a panel of human tasters who were subjected to standardized compounds—for example, urea, quinine, and caffeine. Each compound was rated on a bitterness scale from 1 to 20: 1 to 4 is not bitter, 5 to 8 is slightly so, 8 to 12 is strong but acceptable, 12 to 16 requires taste masking, 16 to 20 is so bitter that masking the taste may not be possible.
Masking is important for several reasons. First, making a drug more palatable can enhance patient compliance. Second, taste may play a role in your drug’s approval. “The FDA gets extremely annoyed by blinded studies where the placebo is so obviously the placebo,” says Mifsud. To avoid eliminating the blind, Alpha M.O.S. has developed a suite of molecules derived from the food industry that, when selected by the finicky e-tongue, can be used to match the placebo to the taste of the active drug.
In addition, taste matching or masking is important to competitor benchmarking and to the creation of generics. “We’ve sold several systems in India just this year where they are trying to copy the actual taste of a drug, the original drug.” Alpha M.O.S. is also learning new tongues, so to speak. A pediatric scale is under development, as is a scale calibrated to the preferences of the Japanese.
Slug it out
Of course, there is such a thing as being too sensitive, which is why new formulations must be tested to see if they
sting, burn, or itch. The current standard for determining this is the Draize Eye Irritation Test: a compound is placed in a rabbit’s eye and see if the eye turns red. It’s a simple test, but increasingly problematic. “The rabbit eye test is severely criticized based on the ethical considerations,” says Els Adriaens, PhD, a postdoctoral student in the laboratory of pharmaceutical technology at Ghent University, Ghent, Belgium. “Also, it’s a subjective test. You’re just scoring redness in the eye, which is not rated the same by you as it is by me.” To solve both ethical and analytic issues, Adriaens is proposing a new model: the hypersensitive slug.
Their outer layer of epithelium is remarkably like the mucosal surfaces of humans, and, most usefully, they also produce slime in response to irritation. And quantities of slime, unlike redness, can be easily and accurately measured. “When you put the slug on a substance that is irritating, it will immediately start to produce mucus,” says Adriaens. “So, we measure the amount of mucus produced and, compared to known standards, we can predict the irritation potency of pharmaceutical formulations.”
The constituents of the slime are also informative. “If there is tissue damage, proteins and enzymes will leak out of the body wall of the slug and we can measure the content.” Her investigations are ongoing, but so far, Adriaens’ data seem at least as good as those generated by the Draize test.
It is relatively easy to dictate where drug activity occurs, but controlling when is another issue. A phase I liposomal drug formulation of doxorubicin, however, aims to do just that by using heat. “Thermodox is temperature sensitive in a very narrow temperature range. The micelle actually opens up when heated in a certain range and releases its contents,” says Augustine Cheung, PhD CEO and chief scientific officer of Celsion Corp., Columbia, Md..
The heat comes from radio frequency ablation (RFA), a method that directly heats tumor tissue using a needle stuck directly into the tumor. Typically used to treat nonresectable liver tumors, the technique is locally effective, but not as useful for adjacent metastasis. “The problem is, we’re not able to heat the tumor high enough,” says Cheung. However, they can raise the temperature reliably within a tight range, say 41 to 42°C. “With Thermodox [and heat] you should be able to dump the payload of cytotoxin not only to the primary tumor region but also to the margin around the ablation zone,” Cheung says. The drug is still systemically delivered, but because it is combined with RFA it now has targeted activity.
“Imagine a soccer ball,” says Cheung, “You have these multiple patches, and then the boundaries between them. We stitched together three thermosensitive synthetic phospholipids with the lipids at the boundary having a constant temperature where it changes from a solid to a liquid.” That temperature is 40.5°C. As soon as that melting point is reached, the boundaries flow, and the drug is released. This occurs in as few as 20 seconds. As the micelles then circulate beyond the heated tumor-target zone, the temperature drops and the boundaries reseal to once again encapsulate any doxorubicin that remains. This liposome and heat combination should not only increase drug concentration in the tumor, but will theoretically help limit systemic toxicity.
Although Thermodox is still in early development for liver cancer, Cheung is focusing on the future. “Once we have proof of concept, we believe that it will open up a huge door for this formulation. We’ll be able to look at encapsulating other cytotoxins, such as cisplatin.” And there are other tumor sites, as well. For Celsion, that will most likely be tumors of the prostate, and beyond that, any tumor site where the technology is applicable.
Filed Under: Drug Discovery