Multiple modes of drug delivery
Imagine particles gliding through your bloodstream, particles in which tiny computers reside—microchips programmed to release several drugs at just the right rate for maximum therapeutic effect. Or better yet, the microchip-containing particle is implanted directly into a target tissue or organ and programmed to release drugs in response to biofeedback. Such drug delivery technologies, because of their convenience, efficiency, and decreased side effects, would quickly replace today’s usual modes of drug delivery—taking several pills several times a day or, even more unappealing to some people, visiting an office to get an injection. And it is not only a matter of convenience and reduced anxiety. In some cases, sustained release is also a more effective way to deliver the drugs—at a slow, steady pace instead of dumping them into the patient’s system with periodic doses of pills or injections. Early versions of controlled drug delivery are already in common use, such as time-release cold tablets and Nicoderm patches for those trying to quit smoking. But such modes of drug delivery are used mostly with small molecules, such as individual peptides. Cutting-edge technologies tackle the real challenge: how to package and deliver proteins and other large complex molecules so that delivery will be accurate, modulated, and effective. Many diseases formerly thought to be untreatable, such as hepatitis C, multiple sclerosis, hormonal disorders, and many cancers, can benefit from protein therapy. But until recently, this required intravenous infusion or frequent injections. With the latest developments in pulmonary delivery and injection of long-lasting doses of proteins, new horizons are appearing for the treatment of such diseases. Proteins present a thorny delivery problem, not only because of their large sizes but because they are notoriously sensitive to changes in their surroundings. Their optimal activity often depends on just the right pH, temperature, and conformational structure. There are several ways to solve the delivery problem, but it requires collaboration among chemists, physiologists, and biomedical engineers. Chemical engineer David Edwards of Advanced Inhalation Research, Inc. (Cambridge, MA), compares the state of the art in drug delivery to the early years of car production, when “lots of car companies with lots of models” rushed to capitalize on technology and capture a share of the market. Edwards finds the atmosphere in the field tremendously electric. “It’s a pretty wild time right now,” he says. “People are seeing things in drug delivery that are working.” Avoiding degradation and phagocytosis The big stumbling block in delivering drugs via the pulmonary system is getting past the lung’s busy ciliated cells, whose job is to continuously sweep the streets clean, so to speak. Normally, large particles such as pollen or soot are kicked out by the escalator of ciliated epithelia in the upper airways, or, if they do get into the deep alveolar regions of the lungs, they are sucked up by cellular vacuum cleaners known as macrophages. Designing particles to carry controlled-release drugs past these lines of defense was not easy. But while Edwards was working on phagocytosis, the process by which macrophages engulf and digest particles deemed as foreign to the cellular system, he noticed that macrophages are fussy about the size of particles on which they will dine. Particles in the size range of 1 to 3 mm are “avidly” engulfed, whereas of particles smaller than 1 mm and larger than 3 mm, Edwards says that “the macrophages just don’t notice they are around.” Armed with this finding, and knowing that the size of a particle carrying drugs for sustained release would have to be large to harbor an effective dose of medication, Edwards set his sights on creating particles that can make it into the deep regions of the lungs and are too large to be of interest to macrophages. The solution came one day, Edwards relates, when he thought, “Well, I’ll make a really light particle.” And he did. The ideal particle, it turned out, was light, large, and porous, and thus not very dense. As Edwards puts it, the particle “flew well” out of an inhaler and landed in the deep alveolar region of the respiratory tract, making it well situated for controlled drug release. The physics of shooting large, low-density particles into the lungs, and predicting trajectories, is similar to the aerodynamics of golf balls. As in the fine art of creating the ideal golf ball, density and shape are played against the force of gravity to optimize the efficiency with which microspheres fly through the bronchial passages and land where they will be most effective. And sure enough, the bioavailability of drugs transported in large microspheres can be much higher than that of drugs given by conventional injection. In the case of estradiol inspired into the lungs of rats, bioavailability approached 87%. In fact, Edwards foresees rapid progress and a time when an inhaler delivering sustained-release drugs will be “a very simple thing, the size of a pill,” as well as disposable and breath-activated, so that the user “won’t sense anything at all.” Perhaps even more important than the convenience associated with inhaling drugs at less frequent intervals is the advantage of lower doses. Because they are delivered more efficiently, drugs entering the body through the lungs can be prescribed at lower concentrations, which is important for many applications, such as the delivery of estradiols to women undergoing estrogen replacement therapy, where picogram levels become important. Edwards says that in addition to the already-tested insulin and testosterone, candidates for inhalation include monoclonal antibodies for treating viral diseases. Diversification of delivery The secret to success in this system is to stabilize the fragile proteins so they will not degrade before they can act on a target. Protein integrity is maintained by a special process in which the drug to be encapsulated is mixed with a stabilizer such as zinc, freeze-dried, and then combined with a common biomedical polymer such as poly(lactide-co-glycolide) (PLG). The development of Alkermes’ polymer system took advantage of technologies that were familiar to regulatory authorities, as in the case of zinc. The amount of zinc is “less than that in normal dietary use” and had already been tested for pharmaceutical use, according to Alkermes’ Stephen Zale. Like all polymers used to construct the microspheres, PLG was chosen because it is both biodegradable and biocompatible. One critical aspect of encapsulating proteins for sustained release is modulation of release at the appropriate rate to achieve the desired pharmacological effect. Release profiles determine how the sustained-release product performs, and they can be adjusted by altering the formulation of polymers. The rate of release of the protein is affected by how quickly the particles become hydrated and erode, and it can be changed to meet the requirements of different proteins by altering the type of PLG polymer used and by adding zinc carbonate. In collaboration with Genentech, Alkermes has successfully encapsulated and clinically tested Prolease microspheres containing recombinant human growth hormone. These Prolease particles were first tested in growth-hormone-deficient adults, in whom levels remained above baseline for weeks, and then in growth-hormone-deficient children. Other proteins, such as alpha-interferon, have been successfully encapsulated in a similar way. Prolease microspheres are delivered by injection, but much less often than in conventional drug delivery. They could improve compliance by reducing the number of office visits, and they also produce less variability—a byproduct of conventional dosing. For certain proteins, it could be possible to reduce the overall monthly dose and thereby reduce the cost to the patient. Prolease clinical trials have been completed through Phase III. Not all the frontiers in drug delivery research lie in sustained release and long-term release. In the treatment of brain tumors, crossing the blood–brain barrier efficiently is essential to effective chemotherapy. Alkermes’ Cereport system operates as an agonist of B2-bradykinin and facilitates the transmission of drugs across the barrier. When a patient is in the hospital for chemotherapy of a brain tumor, the use of Cereport technology, now in Phase II trials in collaboration with Alza, can greatly improve the efficiency with which drugs are delivered. According to Bartus, Cereport was one of Alkermes’ first technologies. It operates by stimulating cerebral receptors to increase the permeability of the blood–brain barrier and create higher short-term efficiency of drug delivery. The overall effect, according to Bartus, is to increase plasma levels to double or triple the therapeutic value. In contrast to the Prolease and Medisorb technologies, which provide sustained release, Cereport technology concentrates on more efficient short-term delivery of drugs, “within the range of 10 to 15 minutes,” says Bartus. Certain drugs, such as sleep medications, “will always require short-duration deliveries,” he says. In addition, because some patients fear injections, there will always be a place for oral delivery of drugs. There will always be a need for parallel platforms, including implants, that can be tailored to individual situations. “It would be a mistake to think that one would completely replace any other,” says Bartus.
Similar implants have been used for the continuous release of drugs for eye diseases. To treat the retinitis that causes blindness in AIDS patients, Control Delivery developed Vitrasert (Figures 1 and 2). These implants, approved and on the market since 1996, are inserted at a rate of about 2500 units per year. The device provides continuous delivery of medication for six to eight months. Other technologies in development at Control Delivery include a second-generation Vitrasert-related device lasting three years and designed to treat uveitis—a disease of the back of the eye—now in Phase II clinical trials Figure 2), and an antiretroviral implant designed to prevent maternal transmission of AIDS. The implant, according to Ashton, is inserted in the infant immediately after birth, and it works to prevent proliferation of HIV while the viral population density is still low, thus preventing the disease from gaining a foothold in the infant.
A new strategy developed by Control Delivery is to make a polymer from linked drugs, thereby eliminating the need for a carrier polymer and making all the compounds delivered to the body pharmaceutically active. In such a delivery system, there would be no waste: It would be like eating chili out of a bread bowl. “Over four hundred combinations of drugs” have been tried in this manner with promising results, reports Ashton. Of course, the ultimate in sustained delivery of drugs is to insert into the organism a new gene that produces the necessary biochemicals as the cell demands them. But gene therapy is much more complicated and plagued with unknowns than the delivery of drugs from an exogenous source in a controlled manner. Bartus admits that gene therapy has always had appeal, but he believes that even if gene therapy technology is in common use someday, there will still be a need for sustained-release drugs. The two lines of attack in correcting biochemical errors “will not be mutually exclusive”, says Bartus. Because the pharmaceutical frontiers are burgeoning with new technology for sustained release and controlled delivery of drugs, what now might seem to be remote possibilities, such as the microchip-containing particle reminiscent of Star Trek, may yet arrive. As Ashton points out, the microchip idea “sounds really sexy,” but it is probably a long way off. He sees the biotechnology revolution as a big impetus in pushing for controlled and localized delivery of drugs, whereby implantation of transfected cells, or “drug factories” as Ashton calls them, may be the logical next step.
Mona Mort is a freelance science writer living in Tucson, AZ. Comments and questions for the author may be addressed to the Editorial Office by e-mail at mdd@acs.org, by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036. Top || Modern Drug Discovery Home Page
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Technologies such as microchips and microspheres are enabling the therapeutic use of proteins.
