By David N. Leff

During the 1980s — biotechnology's first 10 years of existence — the FDA approved 11 recombinant therapeutic proteins.

First in line was human recombinant insulin (OK'd in October 1982), followed, among other molecules, by human growth hormone (October 1985), alpha interferon (June 1986) and erythropoietin (June 1989).

These cloned medicinal proteins all have one thing in common: frequent needle injection to get them into a patient's body.

For all except human growth hormone (hGH), those injections are a life-or-death imperative. For pathologically short children and their parents, a daily injection of hGH instills the hoped-for difference between a lifetime of much-lower-than-average height and one of near-normal stature.

There are some 20,000 such under-height children in the world today.

"In general," observed biochemical engineer Stephen Zale, "for any drug right now that might have a therapeutic benefit but must be injected every day, there are going to be certain indications where the inconvenience may outweigh the benefits. So the drug may just not have a market because of that.

"But if there's a more convenient way of administering the protein," he added, "patients might tolerate an injection at some more sustained period, so maybe it would find an expanded market." Zale is vice president of formulation development at Alkermes Inc., of Cambridge, Mass. This company has developed, and is clinically testing, just such a sustained-release form of human growth hormone.

Zale and Alkermes' senior vice president of neurobiology, Raymond Bartus, are co-authors of a paper in Science dated Aug. 21, 1998. Its title is "Sustained delivery of proteins for novel therapeutic products."

Trade-named "ProLease" by Alkermes, the protein is a sustained-release formulation of the human growth hormone developed in the early 1980s by Genentech Inc., of South San Francisco. The two companies have a collaborative agreement dating from January 1995, and extended in November 1996. (See BioWorld Today, Nov. 15, 1996, p. 1.)

Thirteen adults deficient in growth hormone received a single therapeutic injection of ProLease in a Phase I clinical trial four years ago. Alkermes CEO Richard Pops said at the time that this was "the first demonstration of ProLease's ability to achieve in humans sustained release and biological activity of large, unstable proteins such as growth hormone — lasting three to four weeks."

Whereupon Alkermes and Genentech mounted a Phase II trial of the drug in 64 GH-deficient children at 12 sites in the United States, followed by an ongoing Phase III study, expected to be completed in the fourth quarter of 1998.

Why Not Insulin? Here's Why

Alkermes is also developing its ProLease product for sustained release of alfa-interferon and erythropoietin, both of which require injections several times a week. Insulin, though demanding self-treatment once or twice a day, is something else.

"In the case of insulin," Zale told BioWorld Today, "the amount you want to deliver varies, depending on what's going on with the diabetic patient biologically. It's not the kind of drug that's taken consistently. You inject insulin when you need it, not all the time."

ProLease differs drastically from other drug-delivery microcarriers such as liposomes, Zale pointed out.

"Liposome carriers function in a completely different way," he said. "Typically, they are good for getting sustained-release durations of only a few days, up to a week at most. Whereas with biodegradable polymers, such as ProLease, durations much longer than that are possible. We've seen release sustained in excess of a month in some products."

At the heart of Alkermes' sustainable-release system is a polymer called poly(lactide-co-glycolide) — PLG for short.

"PLG's traditional use," Zale said, "is in biomedical devices such as bone screws, dental implants, biodegradable surgical sutures. In fact, it's used in quite a number of applications that long predate sustained release of small-molecule or macromolecular drugs."

The way the growth hormone protein is incorporated into the PLG carrier, Zale recounted, "is that first of all we turn it into a lyophilized powder. "That powder is then suspended in a polymer solution in organic solvent, and the suspension is atomized to create droplets," he said. "The droplets are frozen with liquid nitrogen, and then undergo a solvent extraction that removes the polymer solvent. At that point they're filtered and vacuum-dried. We wind up with porous polymer particles that contain freeze-dried protein particles dispersed throughout them.

"The microspheres are injected," he said, "either subcutaneously or intramuscularly, depending on the characteristics of the specific drug of interest. Growth hormone is administered subcutaneously."

Drawbacks: Dose Volume, Variable Daily Need

Zale cites "two primary limitations" to which ProLease is subject:

"There are going to be certain things for which it will be applicable, and others where it won't," he said. "One of them is the dose. If you need to deliver a massive amount of a certain drug over a certain period of time, it may be more than you could adequately or reasonably expect to deliver in an acceptable volume of microspheres.

"That would be one drawback," he went on. "The other would be the limitation mentioned in the case of insulin, where sustained delivery is not desirable or optimal."

Zale continued: "We originally developed ProLease with therapeutic proteins in mind, but it's probably good for macromolecules in general. We can even deliver small molecules with this system," he concluded. "It's just that advantages over other encapsulation processes are more evident with macromolecules."

Looking farther into the future, his paper in Science suggests that "it is even conceivable that microelectronic chips might be interfaced with the injected polymer mass to provide programmed control of protein release."

Zale's comment: "To my knowledge, this has yet to be demonstrated." *