As scientists in academia and industry invent new ways to give medicines to patients, the biotechnology and pharmaceutical industries are promising to develop drugs of the future that are better targeted to a patient's disease and can be more easily administered. A selection of patches, nasal sprays, pumps, liposomes, and viral vectors is now making its way through the pharmaceutical pipeline, and these various technologies may soon render the "spoonful of sugar" obsolete.
To make drug delivery needle-free, researchers have found ways to bypass drug absorption barriers in the skin and mucosa. Key advances in chemical formulation have enabled the development of medicines that are absorbed through the skin or that can be inhaled into the lungs.
In addition to being user-friendly, some new drug-delivery systems have made treatments more focused. With several new techniques, higher concentrations of drugs can be delivered to specific diseased tissue, which allows greater potency and less toxicity to healthy tissue. By making drugs more palatable, researchers hope to improve patient compliance and even to lower the costs of hospitalization.
About 10% of hospital admissions are said to result from noncompliance with drug regimens. "Anything that results in fewer administrations by physicians has significant economic advantages," noted Mark Ratain, professor of hematology and oncology and chairman of the Committee on Clinical Pharmacology at the University of Chicago. Advanced drug-delivery technology generates an estimated $10 billion in sales revenue annually. Accordingly, Ratain cited a motivation for profit in drug delivery. "What's driving this R and D is money," said Ratain. "It's a way to patent-protect an old drug; you patent the reformulation."
Regardless of the motivation, researchers have developed several innovative drug formulations. Most novel drug-delivery systems have stemmed from work on new polymers, lipid vesicles, cyclodextrins, pro-drugs, and viral vectors.
By being linked with a polymer, the drug slowly diffuses into the bloodstream over a long period. Levonorgestrel implant contraceptives and injected complexes that release luteinizing hormones are examples of polymers that produce sustained drug levels. Polymer-linked drugs that are deliberately oversized can also better target diseased tissues by escaping through leaky microvasculature and then entering cells by endocytosis. In a model of melanoma, this approach has enabled researchers to achieve levels of the antineoplastic drug doxorubicin that are up to 70 times higher in tumor tissue than those achieved with conventional formulations. Researchers are also perfecting drug-polymer complexes that are linked to antibodies for "active-tissue targeting."
Some polymer systems can be rendered "smart" (that is, sensitive to a tissue environment). Thus, a drug-polymer complex can be designed to undergo a conformational change or enzymatic breakdown that results in release of the active drug only under certain conditions. Drug-polymer complexes that release insulin after sensing glucose, or naltrexone in the presence of morphine, have been described in the literature and may become clinically practical in the future.
Similar advances in chemistry have also allowed many drugs to be administered through the skin. "It's primarily a polymer-based approach," explained Russ Potts, executive vice president of research at Cygnus Inc. in Redwood City, California, in discussing his company's transdermal drug-delivery method. "You take medical adhesives and dissolve drugs in them. You apply the drug to the skin, and it diffuses." Drug delivery through the skin has the advantage of maintaining consistent blood levels. Patches that can be worn for several days also appear to help compliance.
According to Potts, the new technology can be economical. Hormones that are effective at low concentrations are good candidates for transdermal delivery systems. But patches are not ideal for delivering the large doses of drugs that are needed in antibiotic therapy and not economical for such low-cost drugs as aspirin.
The liposome is another construct that serves as an envelope for active drug particles and can, like polymers, deliver high concentrations of drugs to infected or neoplastic tissue. Liposome delivery systems are similar to polymer systems but the drug is encompassed by a vesicle instead of being physically linked to a polymer. In liposomes, a hydrophilic drug can be trapped in aqueous channels that course between successive phospholipid bilayers, whereas a hydrophobic medicine can reside within the bilayer itself. The nontoxic, nonimmunogenic bilayers dissipate, allowing slow diffusion of the active medicine into the tissue. Liposomal amphotericin is widely used, and liposomal formulations for daunorubicin and doxorubicin were recently approved by the Food and Drug Administration for treatment of HIV-associated Kaposi sarcoma.
"The philosophy is greater efficacy with lower toxicity," said Lora Armstrong, director of drug information services at the University of Chicago hospitals. "The drug is not free in the circulation," she said, explaining the formulation's reduced toxicity. Liposomes can have a large capacity for carrying drugs, and they accumulate in inflamed tissue where endothelial barriers break down. Researchers are also exploring ways to target liposomes for neoplastic cells. "If you can increase the amount of drug in the tissue, you can theoretically increase the kill," Armstrong asserted.
Another chemical innovation currently being used for drug delivery involves the taming of a naturally occurring class of molecules known as cyclodextrins, which were once too toxic to be used in medicines. A cyclodextrin is 7 dextrose units held together by a lipophilic core and a hydrophilic exterior, explained Valentino Stella, University Distinguished Professor in Pharmaceutical Chemistry at the University of Kansas and director of the Higuchi Bioscience Center for Drug Delivery Research in Lawrence, Kansas. "It takes an insoluble drug and forms an inclusion complex."
Stella described how the molecules, which were first discovered in the 1890s, were adapted for medical use. "Orally, cyclodextrins are fine, but with injection, they are nephrotoxic ... we engineered a modification of cyclodextrins to decrease their toxicity. They are not delivery systems, they are enabling systems." Because they are safe solubilizers, cyclodextrins are used in formulations of antipsychotic drugs, in a new formulation of itraconazole, and even in Shiseido perfumes.
Stella's team is also developing pro-drugs like fosphenytoin. Pro-drugs are therapeutically inert when administered but become bioactive at or near the site of action in the body. Fosphenytoin is to be sold as cerebyx, a reformulation of the anticonvulsant phenytoin that can be given safely by intravenous injection. Conventional phenytoin can cause cardiovascular collapse when given parenterally. The pro-drug concept is popular: About 15% to 20% of new drugs that are approved are pro-drugs.
According to Stella, the Higuchi group would also like to contribute to the area of gene delivery. "We're not competing with the big boys in gene therapy," he said. "We're focusing on DNA fragments for vaccines." Institutions that are committed to meeting the gene therapy challenge have faced their own drug-delivery problems, and the progress is gradual. Physician-scientists have devoted attention to gene replacement in monogenic deficiency diseases, such as cystic fibrosis, and to many strategies for manipulating the genomes of cancer cells.
Getting the right DNA into the right tissue is the challenge. "The vector delivery systems can be broken down into two areas: viral and nonviral. Viral is the dominant use because viruses are the most efficient parasites," according to Nelson Wivel, deputy director of the Institute for Human Gene Therapy at the University of Pennsylvania School of Medicine in Philadelphia. Wivel said that early work using disabled retroviruses failed because of the inability of retroviruses to infect nonreplicating cells. Adenovirus vectors are now more common, although they are more vulnerable to host immune systems and their longevity of transcription is less.
Nonviral vectors for gene therapy, such as liposomes that are combined with plasmid DNA, have also been studied. According to Wivel, the efficiency of expression is very low because many of the liposomes are absorbed by cells and degraded. "We don't have any targeted vectors," he commented. "Tissue-specific targeting is the Holy Grail of this field."
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Diabetes Treatment Mechanisms
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The heritable disease that has received the most attention from drug-delivery researchers is diabetes. Over the years, researchers have tried various approaches to introduce insulin into the bloodstream of diabetic patients and to achieve predictable levels that might mimic the secretion of insulin in a human pancreas. Insulin has been given by oral and nasal routes, but neither has been shown to be clinically practical. Intranasal insulin relied on "enhancers" to improve mucosal absorption, but the enhancers, in some cases a bile salt, proved to be too irritating.
Implantable insulin pumps that provide a basal rate of insulin secretion and can be directed by remote control to give boluses of insulin at mealtimes may finally become popular. Recent literature suggests that these pumps can control blood sugar as well as intensive insulin injection regimens can. Endocrinologists have long recognized that diabetes can best be controlled with meticulous dietary compliance and frequent doses of insulin.
The most current innovation in diabetes treatment, however, is inhaled insulin. Two California biotechnology companies have developed competing insulin-delivery devices that take advantage of the lungs' design as a diffusion membrane. John Patton, vice president for research for Inhale Therapeutic Systems in Palo Alto, California, explained that his company's device uses a dry, powdered insulin that is turned into a cloud by a pulse of compressed air, inhaled deeply into the lungs, and absorbed.
"The powder allows you to get a lot of medicine in one puff," he said, "whereas with aerosolized liquid systems, you have to take about 50 puffs ... The reproducibility is identical to injections." When asked about lung irritation, Patton would not divulge the compound's ingredients but asserted that the powder was safe. "The additives are approved for the lungs. There are no enhancers-no secret sauce." Inhale Therapeutic Systems, in partnership with Pfizer, will begin phase III clinical trials on inhaled insulin this year.
Amid the interest in new drug-delivery technology, a few pharmacists and pharmacologists have voiced concerns about efficacy and cost. "The new technologies definitely offer advantages," said Armstrong, "but can we afford them? Hospital administrators are extremely fearful because the cost can be so high." In the case of insulin, studies suggest that use of an insulin pump could cost 2.5 times as much as a treatment program that consisted only of multiple injections of insulin. And intrapulmonary insulin, because of its lower bioavailability, will almost certainly be more expensive than injected insulin. Even the new systems that rely on polymers or liposomes are expensive. Armstrong cited liposomal amphotericin as an example; it can cost 50 times more than the conventional formulation.
Some researchers worry that not every invention in drug delivery confers a worthwhile clinical advantage. "Liposomal anthracyclines have activity," said Ratain, "but there has not been a randomized, controlled trial between liposomal and nonliposomal drugs."
The new polymers, liposomes, patches, and aerosols may spark new outcomes research that considers the full cost of disease and weighs the advantages of needle-free medical therapy. "I have not seen the data showing that liposomal amphotericin might be cost-effective," asserted Joseph Paladino, director of pharmacokinetics and pharmacoeconomics at the Suburban Division of Millard Fillmore Hospital in Buffalo, New York. "I haven't seen a liposomal versus regular amphotericin randomized trial," he added. "Who's going to sponsor it? Unless the innovator company thinks they're going to win, they probably won't sponsor a pharmacoeconomic study."
-Paul T. Kefalides, MD
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