End of the Needle

Just a spoonful of proteinoids helps the medicine go down.

By Rick WeissJul 1, 1992 12:00 AM


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In the beginning Robert Rosen created a kind of primordial soup. Mimicking origin-of-life experiments performed in the 1950s, he concocted a stew of amino acids, the building blocks of proteins, and boiled them under an acrid nitrogen atmosphere. He cooked and evaporated and extracted and synthesized. Then he looked down at what he had created--shimmering microscopic spheres made of a proteinlike material--and he said to his boss, It is good.

The year was 1986, and the idea was to make fish oil more palatable by packing the vile-tasting vitamin supplement inside tiny, flavorless spheres that could slip uneventfully past the taste buds. Rosen’s boss at that time, Solomon Steiner, the head of a small biological testing lab in New York, thought such a product would make his company rich. But Rosen, a biophysicist working as a consultant to the lab, had other ideas. I never took fish oil seriously, he says. You’d have to deliver so much of it--at least a tablespoon--in order for it to be effective. So I started to think about things that might be more appropriate.

And what Rosen thought about was insulin. The hormone that regulates blood sugar normally has no hope of surviving the harsh conditions in the stomach. Enzymes in the digestive system break it down. That’s why diabetics, who don’t have enough insulin, must take it by injection rather than as a pill. Rosen, a diabetic himself, has definite opinions about needles: I’d love to take a pill instead of a shot. So he filled his bubbles with insulin instead of fish oil.

And Rosen looked again at what he had created, and he thought about what it might be worth (billions of dollars, according to some estimates), and he told Steiner to forget about fish oil because there are a lot more diabetics looking for ways to avoid their daily injections than there are people in need of a tastier fish-oil pill. Steiner took the insulin-filled spheres and squirted them down the throats of some laboratory rats. The rodents’ blood-sugar levels plummeted. Steiner’s dreams of profits went sky-high.

If they work as well in humans as they do in animals, these microscopic spheres may signal the genesis of a remarkable new era of drug delivery--one in which medicines now administered by injection will become available as simple little pills. The key to the microspheres’ potential is their ability not only to withstand the hellish environment of the human gut but also to deliver their cargo exactly where it’s supposed to go. After protecting their precious contents against the onslaught of digestive enzymes, the microspheres move into the relative safety of the small intestine. Not until then do these biological smart bombs release their therapeutic payloads, which are absorbed intact into the bloodstream.

Pharmaceutical manufacturers have been desperately searching for just such a system, because most of the new drugs they are now developing cannot withstand the acid test of oral delivery. The problem stems from a key difference between the newer drugs and those developed during the past couple of decades. Most of the older pharmaceuticals, such as morphine and penicillin, are made of organic compounds that can survive in the stomach. They aren’t food, says Rosen. We haven’t evolved the ability to digest them. In contrast, the newest medicines coming down the drug-development pipeline are potent proteins derived from genetically engineered cells reared in the laboratory. And proteins are held together by shared groups of molecules known as peptide bonds, which are very susceptible to digestive enzymes. To the stomach, says Rosen, they’re just meat.

They’re much more than that, of course. Recombinant human growth factor, which helps children with hormonal imbalances grow to their full potential; immune-enhancing colony-stimulating factors and cytokines, which muster tumor-chomping white blood cells in record numbers; blood-clot- preventing compounds that rescue cardiac muscles following a heart attack-- all are proteins and are therefore unlikely to survive in the human stomach. That leaves syringes--universally unpopular and entirely unaffordable in many parts of the world--as the only means of getting these drugs safely into the blood.

When Rosen, who now works at Dalhousie University in Halifax, Nova Scotia, created his insulin-filled spheres, he was consulting for Emisphere Technologies in Hawthorne, New York. The lab was then known as Clinical Technologies Associates, a fledgling, privately held company that performed animal and human testing of experimental drugs for pharmaceutical developers. In the mid-1980s the company’s then president and CEO, Steiner, decided the lab ought to have a product of its own. He settled on the quirky goal of developing a good-tasting fish-oil supplement. That meant something had to surround the fish oil. Steiner started pushing Rosen for suggestions.

Rosen was familiar with the experiments performed by biochemist Sidney Fox, who in the 1960s was one of several laboratory scientists attempting to create life from scratch by throwing together amino acids in an environment that mimicked Earth’s pre-biotic conditions. The amino acids didn’t come together in combinations we recognize as proteins, but they did string together. Fox called these creations proteinoids.

Fox also found that proteinoids, when dumped into water, came together in tiny spheres. And when they did, these spheres spontaneously encapsulated organic material floating around in the aquatic environment at the moment of their creation.

It seemed a bit like magic, and to this day no one is sure how this happens. Rosen, along with other biophysicists, speculates that it has a lot to do with the various electric charges carried by the proteinoids. It’s a rule of thumb in nature that opposite charges attract and identical charges repel. Proteinoids have small molecules, such as hydrogen, branching off them at various points along their length, and these molecules carry charges. Some areas of the proteinoid end up with an abundance of negative charges, while others have a lot of positive charges. These areas pull on oppositely charged areas in other proteinoids, and before you know it a bunch of these man-made chains glom onto one another.

But what makes them form a sphere? The capacity to form these spheres is almost unknown, Rosen says. Biological proteins don’t do this. Rosen suspects proteinoids behave this way because they’re not all created equal. Some, he suggests, are attracted to water, others are repelled by it, and some are sort of in between. That provides them with a basis for organization. They get driven into a geometry where everything is ‘happiest,’ Rosen says. That’s what holds them together. It’s not some sort of lock-and-key interaction. Rosen says proteinoids attracted to water may arrange themselves with their heads pointing in, toward the water in the center of the sphere; those repelled by water point out; and the indecisive proteinoids form the middle of what then turns into a relatively thick membrane.

Fox had shown that these spheres resist proteases--digestive enzymes. He’d also shown, says Rosen, that if you formed the spheres in an environment that contained organic material, the spheres would pick it up. Fox had even shown that it was possible to take advantage of the electric charges of the proteinoids and design spheres that reacted in different ways to different environments. Rosen built on the foundation that Fox had laid. He repeated Fox’s work, but he chose his amino acids on the basis of the electric charges they carry. He knew, for example, that aspartic acid and glutamic acid are positively charged, and therefore a proteinoid made predominantly of those amino acids carries more positively charged areas than negative ones. Because of the complicated way that proteinoids fold up and join in a sphere, most of these positively charged areas end up on the outside.

That, Rosen thought, would be a big advantage in the stomach, which contains acids that have a lot of positively charged hydrogen ions. Because of their positive charges, these ions wouldn’t attach to the spheres, thus preserving the integrity of the structures. But--and this was the key to his scheme--an environment with negatively charged hydroxyl ions would have the exact opposite effect. These ions would attach to the sphere and begin to tear it open. And the end of the small intestine, as well as the bloodstream itself, has a lot of negatively charged hydroxyl ions. A sphere with these characteristics, Rosen concluded, would resist attack by acids in the stomach and survive intact until it passed into the intestine and the bloodstream, where it would dissolve, releasing its contents.

The procedure Rosen used to make the first insulin-containing proteinoid spheres in 1986 is essentially the same simple technique used at Emisphere today. The centerpiece is a cylindrical glass vessel 18 inches high and 9 inches in diameter, sitting unobtrusively on a countertop. With the loose panache of a short-order cook, an Emisphere technician pours a dry powder of amino acids through a valve into the vessel, which is filled with argon gas (argon, it turns out, works better than the nitrogen that Rosen used at first). The technician heats the whole thing to about 400 degrees for several hours and ends up with a dark, viscous liquid that looks a lot like honey. That’s all. It’s like making chili, quips the company’s executive vice-president, Sam Milstein.

This liquid is then poured into another vessel, mixed with a solvent, and finally evaporated with a vacuum; left behind are clumps of amber-colored crystals resembling brown sugar. An additional processing step pulls out any remaining oils, creating the final product: a fine, tan powder that’s actually a collection of proteinoids.

Technicians dissolve this powder in water; while this is going on, they mix into citric or acetic acid whatever drug they wish to encapsulate. When the proteinoid-saturated water and the acid solutions are brought together, the proteinoids spontaneously fold into seamless, microscopic spheres, enveloping some of the drug-containing fluid. All that remains is to run the solution through a filter that traps the spheres, which are then freeze-dried. Millions of these microspheres will fit in a single teaspoon--or in a pill, which is how the company packages them.

Emisphere has been quick to capitalize on the discovery. The company is conducting tests not only on insulin but also on heparin, the widely used clot-dissolving compound. It already has formal agreements with three major pharmaceutical manufacturers to develop oral delivery vehicles for various injectable drugs, and it’s negotiating with at least ten others.

It remains to be seen whether proteinoids represent an ideal solution. With the exception of a few technicians who have swallowed mouthfuls of empty ones (nothing happened), they remain untested in humans. Moreover, they will have to compete with other alternative means of drug delivery now under development, including nasal sprays, battery-powered transdermal patches, and implantable pumps. But because proteinoid microspheres are relatively easy and inexpensive to make and, most important, can be taken orally, many researchers rank them among the more promising products currently under investigation by drug delivery specialists.

Much as it would like to, however, Emisphere may not develop the first oral delivery system for traditionally injectable drugs to be approved by the Food and Drug Administration. In Cambridge, Massachusetts, researchers at a biotechnology company called Enzytech are experimenting with a chemical component of corn gluten--a naturally occurring protein--as an acid-resistant coating for standard doses of otherwise injectable drugs. These corn-gluten containers, called nanospheres, are less than a micron in diameter.

Unlike the smart-bomb spheres made by Emisphere, Enzytech’s corn- gluten derivative doesn’t specifically sense the acidity or alkalinity of its environment; it simply protects its contents long enough to allow a substantial portion of the dose to get absorbed into the bloodstream. Nanospheres have potential advantages over proteinoids. For one thing, the natural grain protein is already widely used in foods and as a coating on some pills, making the FDA approval process likely to proceed more smoothly. Preliminary studies of nanosphere-encapsulated insulin and erythropoietin (a red blood cell growth factor that helps patients with kidney diseases) in monkeys have been very impressive, says MIT drug delivery specialist Robert Langer, who cofounded Enzytech. Human trials could begin as early as this fall.

But Emisphere’s proteinoids, which can be custom designed for different types of drugs with different release points, may ultimately prove more adaptable than nanospheres. The company has already tested nearly 400 varieties. Also, Rosen points out, proteinoids have potential applications beyond oral drug delivery. When filled with immune-stimulating fragments of bacteria or viruses, for example, the microspheres may prove useful as oral vaccines. With traditional vaccines you need somebody with a needle, Rosen says. This could completely change the way people look at vaccination.

Only time and a lot of testing will tell whether proteinoid technology represents the dawn of a new era in drug delivery, says Robert Silverman, chief of the diabetes program at the National Institute of Diabetes and Digestive and Kidney Diseases. But if proteinoid spheres prove safe and effective in clinical trials, he says, then one thing’s for certain: They’ll sell like hotcakes.

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