- Email: [email protected]
Getting under the skin
OPINION
Getting under the skin The needle and syringe may be on their way out as materials scientists begin to find better ways of delivering drugs through the skin. Mark Kendall | The University of Queensland, Australia | [email protected] The mapping of the human genome1 in 2001 has provided us with a means of deciphering the complex functions and interactions of our genes, chemicals, proteins, and cells. This understanding is being applied to develop advanced sensors and drugs for monitoring and treating major diseases. Consequently, an explosion of new drugs is expected in the next ten years. How will they be delivered effectively to the body? The most obvious and convenient drug delivery routes are via ingestion or inhalation. However, these are frequently inappropriate because drugs must survive the harsh environments of the gastrointestinal tract, lung lining, and the first-pass metabolism of the liver. As a result, the most common delivery route is the needle and syringe, a method invented in 1853. Despite being around for more than 150 years, the needle and syringe is far from perfect. Let’s start with needle-phobia. Most of us do not like needles and, with many, needle-phobia can be a major impediment to the provision of important vaccines and drugs. But of greater concern is the risk of cross-contamination through needle-stick injuries in health workers. It is estimated by the World Health Organization (WHO) that one billion vaccination injections are administered through national immunization programs each year, and up to 30% of these injections are thought to be unsafe2. The primary risks are infection with hepatitis B and C and HIV. Consequently, effective needle-free vaccination strategies are a major priority of international groups and organizations, such as the WHO and the Global Alliance for Vaccines and Immunization (GAVI). However, the biggest limitation of the needle and syringe is that the delivery route simply does not work in the prevention, treatment, and monitoring
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of a range of currently untreatable diseases. This is because the needle and syringe is literally too blunt an instrument to deliver new-generation drugs and vaccines (e.g. DNA vaccines) to richly abundant key skin cells that reside within a tightly-defined location about a hair-width (~40 µm) below the skin surface3. Immunologists have shown that these cells – called antigen-presenting cells – are very important in inducing strong immune responses in the body4. The challenge for engineers and materials scientists is to produce effective technologies for targeting these key cells just below the skin surface. Initially, materials scientists were slow in responding to this need. Up until about 15 years ago, the key needle-free approach for drug delivery to skin was the diffusive patch. Most of us are familiar with the diffusive patch from well-marketed nicotine products, but it has also had great success in delivering many other drugs. As the name implies, drug diffuses through the skin’s tough outer layer of dead cells, called the stratum corneum. This works well for small (< 500 Da) lipophilic molecules like nicotine. But many of the newer drugs and vaccines are much larger – sometimes in the megadaltons range – and just simply do not diffuse into the skin. Working collaboratively with biologists and clinicians, engineers have applied aerospace technologies to help solve this problem. In particular, high-speed compressible flow and other rocketbased technologies have been applied to deliver drugs and vaccines ballistically into the skin. One embodiment is the liquid-jet injector, which directs a narrow (~100 µm) jet to the skin at ~100-200 m/s that breaches the outer skin layer ballistically. This needle-free approach often delivers the jet deeper into the skin layers, making contact with the underlying nerve endings in the dermis – so it can
DECEMBER 2006 | VOLUME 9 | NUMBER 12
be quite painful. Liquid-jet injectors are currently being commercialized by BioJect. A more precise needle-free alternative directly descendant from rockets is the gene gun (otherwise called biolistics). In the gene gun, biological agents are reformulated as dry microparticles (~2 µm in size) and accelerated in a supersonic gas jet to give sufficient momentum to penetrate the skin and achieve a pharmacological effect5. Typically, the microparticles impact ~1 cm2 of skin at a speed of ~600 m/s – about the cruising speed of a Concorde aircraft. The method has achieved strong immune responses for DNA vaccines and is being commercialized by PowderMed, which is conducting many clinical trials (e.g. for influenza6). Looking forward, the recent explosion of microand nanotechnologies holds great promise in further advanced needle-free drug and vaccine delivery systems. For example, nanoparticles have been shown to diffuse through the stratum corneum, making them a potentially useful drug carrier platform. Furthermore, developments in microelectromechanical systems are opening up new opportunities to make needle-free targeting structures, such as micro/nanosized needle patches that reach the key skin cells for improved vaccines.
REFERENCES 1. Lander, et al., Nature (2005) 409, 860 2. World Health Organization, In Safety of injections, Facts & Figures Fact Sheet No. 232, (1999) 3. Kendall, M. A. F., Vaccine (2006) 24, 4651 4. Chen, D., et al., Expert Rev. Vaccines (2002) 1, 265 5. Kendall, M. A. F., Shock Waves J. (2002) 12, 23 6. Drape, R. J., et al., Vaccine (2006) 24, 4475
Getting under the skin The needle and syringe may be on their way out as materials scientists begin to find better ways of delivering drugs through the skin. Mark Kendall | The University of Queensland, Australia | [email protected] The mapping of the human genome1 in 2001 has provided us with a means of deciphering the complex functions and interactions of our genes, chemicals, proteins, and cells. This understanding is being applied to develop advanced sensors and drugs for monitoring and treating major diseases. Consequently, an explosion of new drugs is expected in the next ten years. How will they be delivered effectively to the body? The most obvious and convenient drug delivery routes are via ingestion or inhalation. However, these are frequently inappropriate because drugs must survive the harsh environments of the gastrointestinal tract, lung lining, and the first-pass metabolism of the liver. As a result, the most common delivery route is the needle and syringe, a method invented in 1853. Despite being around for more than 150 years, the needle and syringe is far from perfect. Let’s start with needle-phobia. Most of us do not like needles and, with many, needle-phobia can be a major impediment to the provision of important vaccines and drugs. But of greater concern is the risk of cross-contamination through needle-stick injuries in health workers. It is estimated by the World Health Organization (WHO) that one billion vaccination injections are administered through national immunization programs each year, and up to 30% of these injections are thought to be unsafe2. The primary risks are infection with hepatitis B and C and HIV. Consequently, effective needle-free vaccination strategies are a major priority of international groups and organizations, such as the WHO and the Global Alliance for Vaccines and Immunization (GAVI). However, the biggest limitation of the needle and syringe is that the delivery route simply does not work in the prevention, treatment, and monitoring
72
of a range of currently untreatable diseases. This is because the needle and syringe is literally too blunt an instrument to deliver new-generation drugs and vaccines (e.g. DNA vaccines) to richly abundant key skin cells that reside within a tightly-defined location about a hair-width (~40 µm) below the skin surface3. Immunologists have shown that these cells – called antigen-presenting cells – are very important in inducing strong immune responses in the body4. The challenge for engineers and materials scientists is to produce effective technologies for targeting these key cells just below the skin surface. Initially, materials scientists were slow in responding to this need. Up until about 15 years ago, the key needle-free approach for drug delivery to skin was the diffusive patch. Most of us are familiar with the diffusive patch from well-marketed nicotine products, but it has also had great success in delivering many other drugs. As the name implies, drug diffuses through the skin’s tough outer layer of dead cells, called the stratum corneum. This works well for small (< 500 Da) lipophilic molecules like nicotine. But many of the newer drugs and vaccines are much larger – sometimes in the megadaltons range – and just simply do not diffuse into the skin. Working collaboratively with biologists and clinicians, engineers have applied aerospace technologies to help solve this problem. In particular, high-speed compressible flow and other rocketbased technologies have been applied to deliver drugs and vaccines ballistically into the skin. One embodiment is the liquid-jet injector, which directs a narrow (~100 µm) jet to the skin at ~100-200 m/s that breaches the outer skin layer ballistically. This needle-free approach often delivers the jet deeper into the skin layers, making contact with the underlying nerve endings in the dermis – so it can
DECEMBER 2006 | VOLUME 9 | NUMBER 12
be quite painful. Liquid-jet injectors are currently being commercialized by BioJect. A more precise needle-free alternative directly descendant from rockets is the gene gun (otherwise called biolistics). In the gene gun, biological agents are reformulated as dry microparticles (~2 µm in size) and accelerated in a supersonic gas jet to give sufficient momentum to penetrate the skin and achieve a pharmacological effect5. Typically, the microparticles impact ~1 cm2 of skin at a speed of ~600 m/s – about the cruising speed of a Concorde aircraft. The method has achieved strong immune responses for DNA vaccines and is being commercialized by PowderMed, which is conducting many clinical trials (e.g. for influenza6). Looking forward, the recent explosion of microand nanotechnologies holds great promise in further advanced needle-free drug and vaccine delivery systems. For example, nanoparticles have been shown to diffuse through the stratum corneum, making them a potentially useful drug carrier platform. Furthermore, developments in microelectromechanical systems are opening up new opportunities to make needle-free targeting structures, such as micro/nanosized needle patches that reach the key skin cells for improved vaccines.
REFERENCES 1. Lander, et al., Nature (2005) 409, 860 2. World Health Organization, In Safety of injections, Facts & Figures Fact Sheet No. 232, (1999) 3. Kendall, M. A. F., Vaccine (2006) 24, 4651 4. Chen, D., et al., Expert Rev. Vaccines (2002) 1, 265 5. Kendall, M. A. F., Shock Waves J. (2002) 12, 23 6. Drape, R. J., et al., Vaccine (2006) 24, 4475