What is controlled drug release and why is it important?
When you take a medicine you may want the drug to all be released immediately or perhaps more slowly over a longer period of time. If we can make a medicine where we control the release then we can tailor our medicines to release at the exact rate we choose that is best for the patient.
We might also want the drug to be released at a certain point in the body so we can try and control the point of release too. If we know our drug should be released in the intestine we can make sure it is protected through the low pH of the stomach and control the release process.
Why is it preferable to take less medication less often?
You can guarantee that patients would rather not take medication at all if they can help it! The more often the patient is required to take their medication the less likely it is they will do it as they may forget or just not bother.
If we can reduce the number of doses per day for a medication then we have been successful, especially if we can get it down to once a day!
If you think about when you’ve been prescribed a medicine that states a dose four times per day, how often have you managed to adhere to the required six hour intervals?
If we don’t take the medicine then we cannot expect it to work, it is that simple really.
Please can you give some examples of excipients?
The excipients we choose mainly depend on the formulation choice, for example, is it a cream, a gel, a liquid, a tablet, a dermal patch or an inhaler?
The most frequently used option is tablets as they are easy to make, stable, socially acceptable, portable and cheap.
If we make tablets we may need to add excipients such as binders, fillers, lubricants and sweeteners. The tablet must stick together when pressed in manufacturing and retain this form when transported yet not stick to the machine or the packaging.
Sometimes, even if we intend the patient to swallow the tablet without biting it open we may coat it in sugar. This helps mask bitter tasting drugs and also makes it easier to swallow.
Every formulation is unique in both the excipients we use and the ratios we choose. A lot of time and money will have been spent on optimising the formulation to maximise the performance of the product.
We always make sure that as much of the drug is available as possible at the right time after being stored for as long as necessary until required.
How can excipients be modified in order to alter drug release?
My research group investigates several groups of compounds that can modify the release of drugs. We can speed the release up or slow it down - it depends on which excipients we use and how we formulate our products.
Some excipients help encourage the drug to dissolve. It is essential dissolution occurs for the drug to be absorbed in the body and therefore, be effective.
In this case, excipients can help speed up the effects of the drug - this is useful if you are making medicines for immediate release, such as painkillers.
If we want the opposite effect, i.e. the drug to be released really slowly over a longer period of time, then we can ‘trap’ the drug and make it hard for the drug to break free from the excipient. This slows down the process substantially.
To do this, we need to form a temporary bond between the drug and excipient. Of course, if the bond is too strong the drug will never be released and the drug will be excreted along with the excipient without having any effect on the patient!
How do you test the effects of changing the excipient on drug release?
There are many ways to test the effects of changing excipients. One of the main concerns is if the drug itself reacts with the excipient as this will not create a stable product. So, we tend to mix the two together and see what happens.
In my research group we use a type of analysis called calorimetry to watch the thermodynamics of the events - from this we can understand what is happening.
We also try to predict what sort of drug release profile you will get from a formulation based on the calorimetric data we get.
We often combine this data with other forms of analysis to develop a full profile for a new drug-excipient combination, perhaps try it at a few different temperatures and concentrations, that kind of thing.
My work is all about predicting what will happen when you give a new product to a patient for the first time using chemical mimics and software systems. The more we can predict the less surprises we will see in the long run.
What are the challenges facing the use of new excipients?
I would say the main challenge is approval, more specifically, the cost of approval. There are many small companies out there who have developed some great new excipients that can modify the release of drugs in all sorts of ways but the cost of developing them further is too high.
This means they then rely on ‘selling’ their ideas to bigger companies rather than being able to develop them further themselves.
What modifications in the formulation process can be used instead of changing the chemicals?
There are several ways people have tried to modify the way they formulate medicines. These tend to give products with different properties. That can be very useful if you are trying to modify a formulation and need to either slow down or speed up drug release.
At the University of Huddersfield we have developed several ways to alter the formulation process, most recently by putting our samples in a microwave. This works well if you can melt the drug or the excipient by heating it up.
If you use a normal oven you get very different products to the ones we get. This can be very useful for industry, especially as we can make our products in a microwave faster, cheaper and more environmentally friendly.
We have developed a special kind of microwave for heating as you need to control the temperature closely.
Why do you think novel microwave irradiation methods produce different results to traditional mixing and heating methods?
We think it is to do with the way the energy is applied to the system, this creates very different types of bonds to form which means we get different release profiles.
There is no doubt that we do see a difference between products, we also see a difference depending on if you have a solvent present or not.
Is it possible to predict how microwaving methods will change the type of product you produce?
I think the effect the microwave energy has on a drug and excipient is still hard to predict. We need to do a lot more work in the area to understand where the relationships exist.
For example, if you vary the drug you may get a change in release behaviour but we are still not clear when this happens and when there is no change.
Can microwaving destroy certain drugs? Can you predict whether this will happen prior to experimentation?
Yes, just like heating any material you can heat it to a temperature where it will start to degrade. We tend to work with materials that can be melted in our systems but hopefully not degrade.
We recently tried to apply our system to a well-known equine drug and it quickly degraded even though we kept the temperatures quite low, we think it was an impurity to blame.
What are your plans for further research in this field?
I am keen to work with small companies that have developed potential new excipients to control drug release and need assistance with their research and analysis. We are able to provide kinetic, thermodynamic, and more general analytical support.
I am working with several companies at present and some of their products are progressing to a stage where they are being considered by larger pharmaceutical partners which is quite exciting.
I certainly think a lot more needs to be done to fully understand the effects that excipient and formulation modifications can have on the final products.
Where can readers find more information?
There are numerous journal articles published each year on the development of novel excipients and formulation processes to create novel products, it is hard to know where to start!
If you work in the pharmaceutical industry and are interested in characterising new excipients or formulation processes I’d be happy to hear from you ([email protected]).
About Dr Laura Waters
Laura completed her PhD at the University of Greenwich in the pharmaceutical research department of Medway Sciences before joining the University of Huddersfield in 2003.
Laura is heavily involved in the Royal Society of Chemistry, former Chair of the local section, a Benevolent Volunteer Visitor and a former member of Council.
She is a member of the Academy of Pharmaceutical Sciences, a Fellow of the Higher Education Academy and a National Public Engagement Ambassador (NCCPE).
Laura has an active research group investigating phenomena at the interface of chemistry and pharmaceutics, developing analytical techniques, characterising chemical interactions and enhancing formulations, all funded through external sources.
Her work in the area of public engagement has led to several recent public lectures and media presentations. For example, in 2011 Laura was awarded the JPAG Analytical Science Award for her pharmaceutical research and the British Science Association Darwin Award for public engagement.
This year she has been appearing on Channel 4 as an expert in pharmaceutical science.
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