Learn about young Irish researchers working in the field of Nanoscience and Nanotechnology, and how their research will contribute to the Irish and global economy.
Nanotechnology in the Pharmaceutical Industry
Teresa Tierney, PhD student, SSPC, University of Limerick
New diseases continually threaten the human race, bringing urgent need for new, improved and affordable medicines. Nanotechnology in the pharmaceutical industry has the potential to revolutionise drug development, bringing significant advances in the treatment and prevention of diseases.
Ireland is a world-leading centre of excellence in the manufacture of pharmaceutical products. In 2009, pharmaceutical exports from Ireland exceeded €19.5 billion making us one of the largest net exporters in the world. However, drug development is an area of high risk and high reward. A newly discovered drug must survive a rigorous testing period of up to 10 years, before being approved as a medicine. Only 1 out of every 10,000 discovered drugs makes it through to commercialisation, which pushes up the average development cost of each successful drug to over $2.6 billion!
So why is the failure rate of potential drug candidates so high, and what can we do to reduce it? Drugs can be unsuccessful for lots of reasons associated with health and safety, or formulation and manufacture. It is estimated that 40% of drugs fail to reach the market due to properties of poor water-solubility. Use of nanotechnology can help to reduce these failure rates, and therefore improve the availability and average development costs of vital medicines.
The most preferred route of drug administration is through the mouth (oral administration). Once taken, the drug must enter the blood stream where it gets transported to its site of action. An orally administered drug in tablet form must dissolve in the gastrointestinal tract before it can pass through the cell membranes to enter the blood stream. Dissolution describes the process by which the particles dissolve. Dissolution can be slow in the case of poorly water-soluble drugs since our bodies are composed of approximately 65% water. Such drugs tend to be eliminated from the gastrointestinal tract before they get a chance to fully dissolve and enter the blood circulation. Consequently, the dose must be increased, leading to increased toxicity levels and side effects. These knock-on negative effects could prevent a drug from being approved as a medicine.
An alternative to dose augmentation is to improve the dissolution behaviour of poorly water-soluble drugs. We can do this by decreasing their particle size. This phenomenon can be observed in everyday life when we consider the faster dissolution of sugar granules, as compared to the same amount of sugar in cube form, when added to a cup of hot tea. Smaller particles have a greater surface area, allowing them more contact with the hot water, and helping them to dissolve faster. The smaller the particle size the more significant the effect. Nanosizing refers to the reduction of the particle size down to the nanometer range. A nanometer (nm) is one billionth of a meter, about 80,000 times narrower than the width of a human hair.
Our work at the University of Limerick involves generating nanoparticles of a model cholesterol-reducing drug, fenofibrate, using an antisolvent precipitation technique. Precipitation is the process by which a solid is separated from a solution which contains a solvent and a dissolved solid. Antisolvent precipitation works by dissolving a drug in a solvent (eg. ethanol) in which it dissolves easily, and adding a small amount of this solution to a large amount of antisolvent (eg. water), in which the drug does not dissolve. Since the solid is no longer soluble in the solvent/antisolvent (e.g. ethanol/water) mixture, it precipitates or falls out of solution in the form of small particles. The difference in the solubility of the drug in the solvent and antisolvent determines how many particles are formed. The more particles formed, the smaller their size will be.
In this way, nanosized particles can be produced. Antisolvent precipitation demonstrates many benefits when compared to other nanoparticle production methods such as milling and grinding. It is a simple, energy/time/cost efficient process, conducted at ambient conditions with good scale up prospects. However, while the nanoparticle formation step is straightforward, the bigger challenge is in preserving the small size of the highly unstable nanoparticles in suspension and during their isolation into a solid form.
Nanoparticles, due to their tiny size, have a much larger surface area than the same mass of larger particles. However, their surfaces are unstable due to dangling, unsatisfied bonds. This instability encourages the particles to cluster together to reduce their surface area, also reducing the dissolution improvement caused by nanoparticle formation. Our work focuses on not only forming the nanoparticles, but also on stabilising the nanoparticles from clustering using other molecules, like polymers, surfactants, sugars, etc. Certain molecules, when introduced to a nanosuspension, can bind to the particle surfaces and prevent the drug nanoparticles from coming in contact with each other. The stability achieved depends on the chemical interactions which occur between the drug and these added molecules.
Using an optimised additive system, we were able to successfully prepare and stabilise nanoparticles of fenofibrate at a size ranging from 200 to 300 nm. These nanoparticles dissolved 230 times faster than the large particles in the original material (333 times bigger). When a comparable dose of original particles and nanoparticles were added to simulated bodily fluids, the original particles took 10 hours, and the nanoparticles took 3 minutes to dissolve completely. This nanoparticle-induced time reduction leads to faster-acting and improved medication. We now hope to use similar approaches to improve the dissolution properties of other water-insoluble drugs which have failed to reach commercialisation on the basis of their poor solubility. In this way, we can utilise nanotechnology as a means of expanding on the range of available medicines, keeping us on course to treat the ever developing diseases which threaten society.
Teresa a member of the Synthesis and Solid State Pharmaceutical Centre (SSPC) at the University of Limerick and is funded by the Irish Research Council with additional funding support from the SSPC and Science Foundation Ireland.
Niamh Creedon, PhD student, Tyndall National Institute
Bovine viral diarrhoea (BVD) is a major contributor to bovine respiratory disease. According to Animal Health Ireland, BVD is one of the world’s most costly bovine diseases with an estimated annual cost of €102 million to Irish farmers. It is estimated that approximately 80-90% of Irish herds have been exposed to the BVD virus. Indications that a herd may be BVD positive include poor conception rates, reproductive issues, a reduced milk yield, calf scours and general herd respiratory problems. However, the majority of infected cattle will show few or no symptoms. Because of this and due to the highly contagious nature of the disease, early identification and diagnosis is critical for herd protection to prevent costly outbreaks.
Current detection methods employed in Ireland’s BVD eradication scheme involve farmers and vets obtaining tissue samples from newborn calves which are then sent for laboratory-based tests (ELISA and RT-PCR). This is a time-consuming process. On average, it can take 7-10 working days to receive the test results back at the farm. During this time, if an animal is BVD-positive, the potential for further infection within the herd is massive! The benefits, therefore, to be derived from on-farm testing with a fast turnaround time are obvious.
To address this, the Nanotechnology group in the Tyndall National Institute in collaboration with our colleagues in Teagasc are developing a cost-efficient nanowire chip sensor, to provide on-site disease testing in cows within 5 minutes. Our sensor works in a similar fashion to existing glucose tests for people with diabetes. We place a drop of blood from the cow on the sensor and get a positive or negative response for BVD – right there, on the farm.
The word “nanotechnology” is becoming more popular in today’s society, but what exactly does it mean and why do we use it? We live on a scale of meters and kilometres so it’s hard to imagine something as small as the nanoscale, but to give you an idea, a sheet of paper is 100,000 nanometres thick. One nanometre is the length that your fingernail grows in one second.
So what is so special about the nanoscale? The reason we use this incredibly small scale is because materials behave differently at this scale, i.e. they can have different physical properties. Also, studying something at the smallest possible scale helps us figure out which are the dominant processes and we can use knowledge to develop devices with increased sensitivity and faster response times. Applying this understanding to engineer to create items at the nanoscale is called nanotechnology. In Tyndall, we are making gold nanowires (about 50 nanometres high and 100 nanometres wide) integrated on a chip to allow us to detect the BVD disease in cattle.
Why are we using nanowires? Well, all the biology we use occurs at the nanoscale so we are able to study the biological interactions at the nanowire with great precision. Our nanotechnology allows us to create the same sensitivity that is possible in the laboratory, but on a portable chip to bring to the farm.
Now lets discuss how the sensor works. To put it simply, a sick animal’s immune system will produce specific antibodies against the virus it is infected with. By attaching the BVD antibody to the gold nanowire on our sensors, the virus, if present in the cow’s blood, will bind to the antibody resulting in a change in signal on our sensor giving a positive test result.
The sensor is BVD virus specific as other viruses present in the cow will not bind to the BVD antibody; this gives a highly selective test for the detection of the virus. So if we consider a healthy cow, the BVD virus would not be present in its blood, therefore nothing will bind to the sensor, hence no change in signal , giving a negative result. An infected animal would give a clear change in signal.
This work is by supported by Science Foundation Ireland under the US-Ireland “AgriSense” project. The project includes collaboration with Teagasc and partnership with the Georgia Institute of Technology, Atlanta and Queen’s University Belfast.