Drug delivery
injection devices. Typically, volume is added to thin out the liquid, and the drug is given intravenously in a clinical setting. This ensures the patient still gets the correct dose, but it’s also inconvenient for them to travel to the hospital and wait there while the IV bag drains. There’s the alternative of using an injection with a bigger needle that has a wider diameter, but this can be more painful – which might make people resistant to taking the drug, especially if they have to administer it at home. To make delivery as smooth as possible for patients, many in the field are investigating how these drugs could be delivered at home via self- injection. But for this to work, they need to figure out how to get smaller volumes of thick fluids through those devices while maintaining the drug’s stability. One approach is to alter the formulation in ways that reduce its viscosity, while another is to use a drug delivery device that provides enough power to push the drug through the skin. However, neither strategy is straightforward.
Reducing viscosity
The simplest way to reduce the viscosity of a fluid is to dilute it. But since the amount of liquid you can use for subcutaneous injections is limited – for comfort, the injection time should be reasonably short, while injecting too much can hurt – there isn’t much wiggle room where it comes to adding volume. What you can do is add ingredients, known as excipients, to the formulation alongside the active pharmaceutical ingredient (API). While they’re considered inert substances, excipients interact with APIs in a variety of ways to help establish the properties a drug needs to be safe and effective, like improving its stability or extending shelf life. For example, an excipient could work to create space between protein molecules, which typically serve as the API within biologic drugs. This helps the fluid flow more freely, explains Shahid Uddin, senior director of formulation and stability at biotech company Immunocore.
Most proteins have a charge, which means they can be attracted to each other. This allows them to come together and form larger structures. “They become bigger, and with everything bigger it’s harder for them to move,” explains Uddin. “The excipient tries to remove that charge.” But choosing the right excipient for the job can be complicated. Because every protein is unique and may behave differently at high concentrations and formulation conditions, there’s no one-size-fits all solution to improve viscosity, says Alana Gouveia, protein formulation scientist at Merck. The amino acid arginine is considered the standard choice for protein formulations, for example, but it doesn’t always work. Scientists must weigh up the properties of excipients alongside those of the API,
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www.worldpharmaceuticals.net
and consider how each substance might behave within a particular formulation. There are plenty of factors at play here: for one, because the forces responsible for protein-protein interactions within highly concentrated liquids that can create viscosity are of the same chemical nature as those that keep an API intact, meddling with them can have negative knock-on effects. This is especially true when the API is an antibody, due to the susceptibility of these molecules to degrade through aggregation. “If you interfere with these interactions too strongly, we could also risk destabilising the antibody itself,” explains Gouveia. Excipients can work synergistically when used in combination. At Merck, Gouveia and her colleagues discovered that using an anionic excipient with an amino acid was more effective at reducing viscosity, while maintaining protein stability, than using either substance alone. However, excipients can only reduce viscosity to a point within a fixed volume, says Uddin. “There are some biophysical limitations, for instance, molecular crowding,” adds Gouveia. In formulations with a very high concentration, there isn’t enough space to prevent proteins from interacting with each other, so the impact an excipient could have is limited. “Another way would be to optimise the amino acid sequence of the protein while maintaining its biological activity and stability during the protein design, in the early development phase,” says Gouveia.
She adds that because the amino acid sequence of a protein may affect how it interacts with other proteins, including in ways that cause viscosity, you could alter the sequence to change that protein’s behaviour. This can also impact the protein’s efficacy, and as such, it requires a deep understanding of protein structure and properties to apply the technique effectively.
9
Changing the viscosity of certain drugs
could allow patients to manage their conditions from home, rather than taking trips to the clinic.
Robert Przybysz/
www.shutterstock.com
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