Smaller is Better

Everybody has heard about using nanotechnology in drug delivery,but not many people—even specialists in drug development—know quite where the new technology fits in. In some ways, this puts pharma in the same league with other everyday industries undergoing major changes, albeit invisible ones, when technologists alter products at the microscopic level. Marketers trumpet nanotech progress in fields from stain-resistant clothing and sports equipment to computer parts and car accessories. Of course, they rarely share details about how the new technology works.

In pharma, nanotech usually creates or "packages" microscopic doses to deliver medication more effectively. These doses are very small. The width of a human hair is approximately 50,000 nanometers, while the width of a DNA strand is 2.5 nanometers. FDA has no definition of (or budget for) nanotechnology, but along with 22 other agencies, it participates in the National Nanotech Initiative (NNI), which was formed in 2001. NNI sets the scale of nanotechnology at about one to 100 nanometers. Many nanobiotech devices are a bit larger, but a recent Google search did not find the word "nanobiotechnology" on fda.gov. When technology in this size range modifies a drug, it generally alters fundamental molecular or biological properties, so that a drug can enter a cell by activating or disabling a particular receptor—or change a key property like solubility.

Nanobiotechnology and the Drug Lifecycle

Elan Corporation estimates that solubility issues slow the development of 40 percent of new drug compounds, often preventing them from entering trials at all. Other drugs lose revenue when the delivery platform proves to be less than patient-friendly or limits its success. If patients are not comfortable taking a drug with a certain delivery, they are more likely to switch to a different drug or not comply with their therapy. More convenient drug delivery increases patient compliance. In addition, new delivery systems keep a drug competitive after patent expiration, even when generics using the old delivery method cut the manufacturer's price by 90 percent. So nanobiotechnological drug delivery can reduce or eliminate revenue losses throughout the drug lifecycle.

Drug Delivery Creates a Market

When most individuals envision drug delivery, they see injections, pills and capsules, inhalation systems, transdermal patches, and so on. Nanobiotechnology differs in that it enhances drug delivery at the molecular level. Some of the first nanobiotechnology products were produced using liposomes and their phospholipid bilayer. These substances—something like little envelopes—encapsulate a small molecule, making it water soluble so that it can more easily enter specific cells. Many companies are developing this technology to aid the delivery of chemotherapy agents directly to cancer cells.

The first compound advertised as a nanobiotechnology drug was Abraxane from Abraxis Oncology. This company attached paclitaxel, one of the most popular chemotherapy drugs, to an albumin nanoparticle. Adding the nanoparticle enabled the manufacturer to eliminate the toxic solvent traditionally used to deliver paclitaxel. Abraxane requires no premedication, has a better toxicity profile, and improves quality of life during treatment for breast cancer. The current success of Abraxane—and the company's nanoparticle albumin—was affirmed when AstraZeneca agreed to co-promote the drug. The enhanced molecule breathes new life into a market once dominated by an inexpensive and patient-unfriendly therapy.

NanoBio Corporation is developing its NanoStat platform for use in a variety of therapeutic treatments, including vaccine delivery. The NanoStat platform is a nanoemulsion created by immersing nanoparticles in oil and water to disrupt membranes on organisms like viruses, bacteria, and fungi. The company has products in clinical trials for herpes simplex I and II, shingles, and onchomyosis. In addition, the platform is being developed for nasal delivery of vaccines and has received funding from the United States government for potential bioterrorism applications.

Nanobiotechnology Manufacturing Techniques

Elan Corporation is one of the most successful nanobiotechnology integrators, with four partnered drugs on the market. Elan's proprietary NanoCrystal technology utilizes a wet-milling technique to reduce the drug crystal size to 1,000 nanometers. At this small size, the greater surface area of the crystals increases the solubility of the drug. The latest company to adopt Elan's technology is Abbott Laboratories, which uses it for TriCor (fenofibrate), a cholesterol-lowering drug. Previously, TriCor had to be taken with food at a higher dose, but this third-generation TriCor allows the patient to take a lower dose at a convenient time. This strategy not only has the potential to improve patient compliance, it has fended off potential generic manufacturers. Generic drug makers can reproduce the active ingredient, but they are not allowed to copy the enhanced nanobiotechnology delivery system. Elan also helped transform Rapamune (sirolimus), a Wyeth drug used to counteract organ rejection, from an oral suspension to a simple pill.

SkyePharma's Insoluble Drug Delivery (IDD) platform is another promising advance in nanotechnology. The new, proprietary technology creates drug particles that range from 40 to 1,000 nanometers, dramatically increasing their solubility. One of its first products, TriGlide, contains fenofibrate, the active ingredient in TriCor, and boasts the same patient benefits. When comparing the two new delivery systems, the main competitive advantage is dosing control—in particular, lowering the total amount of the drug in the patient's system. For fenofibrates, the NanoCrystal Technology by Elan has succeeded in lowering the overall TriCor dose more than TriGlide by SkyePharma.

Complex Solutions Deliver Hope

Dendrimers are among the most widely studied molecules in all of chemistry and nanobiotechnology. These exciting molecules are extremely flexible and offer a variety of applications. Dendrimers consist of three basic parts: a core molecule, the branching molecules, and the surface molecules. These combine to form a spherical shape that creates a large surface area. Large dendrimers can form into spheres that encapsulate poorly soluble molecules. Scientists manipulate the branching molecules to form a dendrimer of a specific size, and attach surface molecules at the end of the branching molecule to give the whole structure the desired chemical properties—hydrophilic, hydrophobic, or electrophilic. Or the surface molecules can incorporate a cell receptor or antigen.

The Michigan Nanotechnology Institute for Medicine and Biological Sciences (M-NIMBS) is at the forefront of dendrimer-based research. The young company has created an extensive catalog of dendrimers with surface molecules useful in therapeutics or delivery.

M-NIMBS has created some of the first biological nanodevices for the treatment of cancer. The goal is to create a dendrimer that can recognize a certain cancer-specific receptor, deliver a therapeutic (lethal) drug, and contain an imaging agent to show the occurrence of cell death. Such a molecule could revolutionize treatment by providing patients with safe mechanisms to destroy their cancer with minimal side effects. While this technology is in very early stages of development and has not reached clinical trials in humans, M-NIMBS is actively pursuing a treatment for head and neck cancer as well as prostate cancer.

Utilizing the principles of dendrimers, StarPharma and Dendritic NanoTechnologies have developed a product that has the potential to drastically reduce the incidence of HIV and Herpes infections. Applied as a gel, their dendrimers bind to the GP120 protein on the surface of HIV, preventing it from binding to T-cells and infecting the individual. The product, VivaGel, has entered human clinical trials and has a potential market entry date of 2008.

Looking Ahead

These and other drug-delivery companies are developing novel ways to improve the delivery of medications. The hope is that they will not only be more patient-friendly, but also more effective. Most of these companies develop technology and then look for companies with existing drugs or drug-discovery capacity to create a partnership. These new-found partnerships are restoring lost revenue opportunities by helping more drugs overcome solubility issues and extending product lifecycles to other new delivery characteristics. Nanobiotechnology is a growing field. Newly approved products demonstrate its exciting potential every year. The future of drug delivery may not be the visible patch, pill, or injection, but rather, molecular characteristics measured in nanometers.

Jason McKinnie is an industry analyst at Frost & Sullivan. He can be reached at pharminfo@frost.com