Nanotechnology Advances in Drug Delivery

Established drug delivery companies, start-ups, and academia are advancing nanotechnology in oral, injectable, transdermal, and implantable systems as a means to improve bioavailability for a variety of drugs.

Nanotechnology at work

Start-up companies as well as established companies are pursuing commercial development of nanotechnology-based delivery systems (see Table I). Elan Corporation's "NanoCrystal" technology, for example, is designed to improve the delivery of poorly water-soluble drugs by transforming them into nanometer-sized particles, typically less than 1000 nm in diameter, which are produced by milling the drug substance using a proprietary wet-milling technique, according to company information. The NanoCrystal particles of the drug are stabilized against agglomeration by surface adsorption of select stabilizers. The result is an aqueous dispersion of the drug substance that behaves like a solution, a "NanoCrystal Colloidal Dispersion," which can be processed into finished-dosage forms.

Table I: Select companies involved in nanotechnology-based drug delivery.

Elan has four products, approved in the United States, which use the NanoCrystal technology: Wyeth's (Madison, NJ) "Rapamune" (sirolimus), Merck & Co.'s (Whitehouse Station, NJ), "Emend" (aprepitant), Abbott Laboratories' (Abbott Park, IL) "Tricor" (fenofibrate), and Par Pharmaceutical's (Woodcliff Lake, NJ) "Megace ES" (megestrol). Elan also has a pact with Abbott and AstraZeneca to use the NanoCrystal technology in developing a combination product of fenofibrate and AstraZeneca's (London) "Crestor" (rosuvastatin). Elan is partnered with Johnson & Johnson (J&J, New Brunswick, NJ) for the NanoCrystal technology in J&J's long-acting injectable form of paliperidone that is under development.

Baxter Healthcare's "Nanoedge" dispersion technology is another example of a commercial nano-based approach. The particle size is reduced to a nanometer size range to increase the surface area, thereby increasing the rate of dissolution by using two complementary processes, homogenization and precipitation.

pSivida (Perth, Australia), which recently signed a $165-million pact with Pfizer for ophthalmic delivery, owns the right to develop and commercialize "BioSilicon," a nanostructured porous silicon for drug delivery. BioSilicon is composed of elemental silicon that is processed to create a honeycomb structure of pores. These pores can be formed into various shapes and sizes and filled with drugs, including small chemical entities, peptides, and proteins, according to the company. pSivida is targeting the technology for formulating poorly water-soluble drugs and for controlled, slow-release drug delivery.

pSivida's lead product using BioSilicon is "BrachySil," a brachytherapy treatment in Phase II trials, which involves the localized delivery of radioactive agents directly into a tumor. The product is licensed to Beijing Med-Pharm Corp. (Plymouth Meeting, PA).

Insert Therapeutics (Pasadena, CA), a subsidiary of the nanotechnology company Arrowhead Research Corporation (Pasadena, CA), is using a nano-engineered polymeric drug delivery system,"Cyclosert," to deliver small molecules and nucleic acids. The system is based on linear cyclodextrin-containing polymers. Insert Therapeutics is licensing the technology to R&D Biopharmaceuticals GmbH (Planegg, Germany) to deliver the anticancer agent tubulysin A. R&D Biopharmaceuticals recently signed a pact with Insert Therapeutics to use the technology in developing epothilones, microtubule depolymerization inhibitors used as anticancer therapies.

Insert Therapeutics is further licensing the technology to another Arrowhead subsidiary, Calando Pharmaceuticals (Pasadena, CA), which develops small interfering RNA (siRNA) therapeutics. Calando's lead drug candidate, CALAA-01, is a nanoparticle containing nonchemically modified siRNA and a transferrin protein-targeting agent formulated with Calando's "Rondel" (RNA/Oligonucleotide Nanoparticle Delivery) technology.

Academia pursues nanotechnology

Researchers at Princeton University (Princeton, NJ) recently developed a new technique, "Flash NanoPrecipitation," which allows for mixing drugs and the materials that encapsulated them, according to a May 2007 university release. Similar mixing techniques previously have been used to create bulkier pharmaceutical products and have proven practical on a commercial scale.

The Princeton-led team, which includes chemical engineering professors Robert Prud'homme, Yannis Kevrekidis, and Athanassios Panagiotopoulos, is the first to apply the technology to create nanoparticles that are 100–300 nm wide, according to the release. Particles in this size range also could improve the delivery of inhaled drugs because they are large enough to remain in the lungs, but too small to trigger the body's lung-clearing defense systems. This trait could maximize the effectiveness of inhaled, needle-free vaccination systems.

In NanoPrecipitation, two streams of liquid are directed toward one another in a confined area. The first stream consists of an organic solvent that contains the drug and polymer, and the second stream contains pure water, outlines the release. When the streams collide, the hydrophobic drug and polymers precipitate out of solution, and the polymers immediately self-assemble onto the drug cluster to form a coating with the hydrophobic portion attached to the nanoparticle core and the hydrophilic portion stretching out into the water. By carefully adjusting the concentrations of the substances and the mixing speed, the sizes of the nanoparticles can be controlled. The stretched hydrophilic polymer layer keeps the particles from clumping together and prevents recognition by the immune system so that the particles can circulate through the bloodstream.

Researchers at the University of Pennsylvania School of Medicine & School of Engineering and Applied Science (Philadelphia, PA) used a cylindrical carrier to sustain delivery of the anticancer drug paclitaxel to an animal model of lung cancer 10 times longer than that delivered on spherical-shaped carriers, according to an April 2007 university release. The research team used skinny cylindrical nanoparticles composed of synthetic polymers to deliver the anticancer drug paclitaxel to human lung tumor tissue implanted in mice. The cylinders have diameters as small as 20 nm and lengths approaching the size of blood cells. The paclitaxel shrunk the tumors, and because the cylinders remained in circulation for up to one week after injection, they delivered a more effective dose, killing more cancer cells and shrinking the tumors to a much greater extent, an improvement over spherical nanoparticles (1).

Magnetic nanocrystalline iron-nickel alloys is another nano-based advance in drug delivery. Researchers at the University of Louisiana at Lafayette (Lafayette, LA) prepared magnetic nickel ferrite nanocrystals coated with the biocompatible polymer polymethacrylic acid (PMAA) and developed methods of hooking the anticancer agent doxorubicin to the ends of the PMAA chains (2).

Nanotechnology: A regulatory perspective

While many definitions for nanotechnology exist, the National Nanotechnology Initiative (NNI, Washington, DC, www.nano.gov), a federal research and development program established to coordinate the multiagency efforts in nanoscale science, engineering, and technology, in which the US Food and Drug Administration (Rockville, MD, www.fda.gov) and 22 other federal agencies participate, specifies that nanotechnology involves: research and technology development at the atomic, molecular, or macromolecular levels, in the length scale of approximately 1–100 nm; creating and using structures, devices, and systems that have novel properties and functions because of their small and/or intermediate size; and the ability to control or manipulate on the atomic scale (3).

The FDA has not established its own formal definition for nanotechology, although the agency participated in the development of the NNI definition of nanotechnology. Using that definition, nanotechnology relevant to FDA might include research and technology development that both satisfies the NNI definition and relates to a product regulated by FDA (3).

To facilitate the regulation of nanotechnology products, FDA formed a NanoTechnology Interest Group (NTIG), which is made up of representatives from all agency's centers (3).

The growing importance of nanotechnolgy in pharmaceuticals was underscored last year by FDA launching the Nanotechnology Task Force, whose mission is to identify and recommend ways to address knowledge or policy gaps to facilitate the safe and effective use of nanoengineered materials in FDA-regulated products. The task force held its first public meeting last October (4), and a report from that meeting is due this year (5).

In 2005, under the National Cancer Institute's (NCI) Alliance for Nanotechnology in Cancer, a initiative encompassing the public and private sectors and designed to accelerate the application of the best capabilities of nanotechnology to cancer, FDA and NCI joined forces under the nano-subcommittee of the Interagency Oncology Task Force (IOTF). Under the IOTF umbrella, FDA, NCI, and now NIST, are leveraging resources and expertise to advance nanotechnology in the context of oncology (5).

References

1. D. Discher, "Shape Effects of Filaments Versus Spherical Particles in Flow and Drug Delivery," Nature Nanotechnology 2 (4), 249–255 (2007).

2. S. Rana et al., "On the Suitability of Nanocrystalline Ferrites as a Magnetic Carrier for Drug Delivery: Functionalization, Conjugation and Drug Release Kinetics," Acta Biomater 3 (2), 233–242 (2007).

3. FDA , "FDA and Nanotechology Products," www.fda.gov/nanotechnology/faqs.html, accessed May 7, 2007.

4. FDA, "Public Meeting on Nanotechnology Materials in FDA-Regulated Products (USFood and Drug Administration Nanotechnology Task Force, Bethesda, MD), Oct. 2006, www.fda.gov/nanotechnology/meetings/transcript.html, accessed May 7, 2007.

5. FDA, "Did You Know: Nanotechnology," www.fda.gov/oc/initiatives/criticalpath/nanotechnology.html, accessed May 7, 2007.