The Interface of Medical Devices and Pharmaceuticals: Part I
This two-part article considers the complexities of developing and commercialising combination products using examples from experience with drug-eluting stents and drug-eluting beads. Part I discusses the technical challenges of developing these products.
Biocompatibles UK Ltd, Farnham, UK
Image: Biocompatibles UK Ltd
The drug eluting stent (DES) has attracted a great deal of attention and is the first example of a combination product with a billion dollar market. Here, the device is implanted to retain patency of the coronary artery in which it is placed; the drug is delivered locally from the stent surface into the artery to deal with the biology of the healing response that may otherwise cause the vessel to re-narrow (referred to as restenosis, which is induced by placement of the device).
In contrast, there is another combination device for intra-arterial delivery of a drug known as the drug–eluting bead (DEB). Here, the device is delivered into the feeding artery of tumours in the liver to block the vessel and starve the tumour of nutrients and oxygen. This hypoxia process will have a biological effect on some of the tumour cells causing them to express survival factors, which is combated by the local delivery of chemotherapeutic agent to kill the cells. This article considers the tribulations of developing and commercialising combination products and uses examples from experience with DESs and DEBs.1
The technical challenges involved in developing and testing a combination product should not be underestimated. The convergence of the two technologies carries its own unique set of considerations. It is not necessarily a simple case of testing the combination device for its drug and device characteristics in isolation, because the properties of the device and/or the drug may be affected by the presence of the other. For this reason, a combination product can potentially be more complex to design and develop than a product that is considered to be a simple union of the two components. Some of the important considerations that need to be addressed include the following:
- Is the device capable of carrying a drug component?
- Can the device carry sufficient drug to be of a therapeutic benefit?
- Can the device modulate the release of the drug?
- How does the device affect the drug and vice versa?
- Does the device still perform its basic physical function?
- If the device interacts with the drug, is the interaction reversible?
- Is the drug stable in the device and vice versa?
- Can the combination product be sterilised to give long term stability of the drug and the device?
Using a DES as an example, often the drug component is combined with the stent scaffold (device) using a polymeric carrier. One of the primary aims of the polymer carrier is to ensure that the drug is evenly distributed over the stent surface and it is often selected for its film forming properties. Furthermore, the polymer carrier is needed to enhance the durability of the active layer so that the drug is not lost in the systemic circulation prior to deployment in the coronary artery. Perhaps most importantly, the polymer is also selected for its ability to help control the release of the drug from the stent once implanted.2 In designing a suitable polymer coating, the following points are amongst many that need to be considered:
- The coating should be designed to be biocompatible and not invoke an adverse reaction within coronary tissue; it should also have long term biocompatibility even if it degrades in vivo.
- The coating should be robust and not delaminate during stent placement and deployment; this is especially important in terms of fragment formation during deployment, which could have significant unintended consequences if sufficient fragments are formed and then embolise vessels downstream from the location of stent deployment.
- The coating should be designed so that the drug component can be released into the coronary vessel at a rate that provides a therapeutic dose to the coronary tissue over an extended time period to reduce the restenosis process.
- The coating and active should be capable of being terminally sterilised.
These points present significant technical hurdles that must be overcome. First, the compatibility of the polymer carrier and the drug should be evaluated to ensure uniform distribution of the drug within the polymer matrices. This does not necessarily mean one must be completely miscible with the other. The Taxus stent employs a polymer coating in which the active paclitaxel is phase separated into submicron sized domains, but which are evenly distributed across the stent surface.3 Second, the effect of the drug on the properties of the polymer carrier needs to be understood and characterised. For example, if the polymer coating is designed to be flexible to accommodate stent expansion, then it is important that this characteristic is not undermined by the presence of the drug. This is also true in relation to the effect of the drug on the adhesion of the polymer matrix to the stent surface. Adhesive failure can result, which can have a number of effects not least the potential to generate particles and the loss of therapeutic doses of the drug in the coating layer. This type of failure therefore, has the potential to change the safety and efficacy of the DES and hence the risk–benefit profile of the device.
Stents have historically been subject to some form of conditioning process to aid their retention when placed onto the delivery balloon catheter. Often the processes used involve the application of heat and/or elevated pressures to the stent and balloon to achieve a secure union between the two components. In the case of a DES, the polymer–drug coating needs to be designed to be flexible to accommodate expansion during stent deployment while being resistant to creep over time, which has been an issue with some stent coatings.4 One way of accommodating the arising stresses is to use a polymer that can undergo sufficient reversible elongation under the conditions of stent deployment. This could be achieved by selecting a polymer with a glass transition temperature (Tg) of approximately 37°C, which would allow the polymer to undergo elongation within the body. The consequence of this design feature gives rise to a further series of considerations including, but not limited to the following:
- the effect of the thermal conditioning steps on coating distribution over the stent struts, adhesion of the stent to the balloon catheter, and on successful deployment of the stent
- the extent of particle formation (size and number) during stent deployment
- the effect of tracking the stent through the coronary artery in terms of drug loss through dissolution in the bloodstream and potential delamination.
The last point is an interesting one to consider, because if the Tg of the polymer is 37°C, then its mechanical and elution properties may be different from those at room temperature. It is, therefore, important to evaluate properties such as drug elution and stent retention under simulated conditions that mimic use in vivo. This example illustrates the degree of complexity that is introduced when multiple components are in combination; each contributes to the number of technical considerations that have to be addressed in pursuit of an optimised product.
Fundamentally, it is important to understand the science behind each component of the combination device and how combining each of the elements affects product performance. Central to this understanding is the design of appropriate in vitro methods that test the device in suitable conditions that simulate clinical use.
In addition to physicomechanical issues, the combination device poses a number of questions associated with its drug delivery properties and the subsequent biological action. Part II of this article discusses the in vitro tests that must be performed to predict product behaviour in vivo using the doxorubicin DEB as an example, shelflife testing of DESs and DEBs, and how to simplify product development.
1. A.L Lewis and M. J. Driver, “The Benefits of Drug–Device Combinations: An Open and Shut Case,” European Biopharmaceutical Review, 82–87 (Summer 2005).
2. B. Balakrishnan, et al., “Intravascular Drug Release Kinetics Dictate Arterial Drug Depositiom Retention and Distribution,” J. Control Release, 123, 2, 100–108 (2007).
3. S.V. Ranade et al., “Physical Characterisation of Controlled Release of Paclitaxel from the TAXUS Express2 Drug–Eluting Stent,” J. Biomed. Mater. Res. A, 71, 4, 625–634 (2004).
4. L. Pinchuk et al., “Medical Applications of Poly(Styrene-Block-Isobutylene-Block-Styrene),” Biomaterials, 29, 41, 448–460 (2007).
Sean Willis is Development Director and Andrew Lewis is Research and Technology Director at Biocompatibles UK Ltd, Chapman House, Farnham Business Park, Weydon Lane Farnham GU9 8QL, UK, tel. +44 1252 732 732, e-mail: firstname.lastname@example.org, www.biocompatibles.com