The Problem with Stents

Our company is involved in developing and manufacturing APIs that can be utilized with drug-eluting stents (DES). Despite ensuring constancy in pharmaceutical composition, we are experiencing issues with variations in drug release during in vitro studies. We are working closely with a stent manufacturer to develop the system, but could surface analysis techniques investigate the problem further?

In short the answer is yes — particularly as the composition constancy is closely monitored. However, before going into the types of analysis that may shed light on your problem, it is useful to understand more about the development of DES.

Technology

Stents are metal mesh tubes that have been used since the 1990s. They are inserted post-angioplasty to treat blocked coronary arteries. Initially, they were simply bare metal tubes that had been passivated and deemed fit to be implanted. At first, these metal scaffolds provided positive results with arteries remaining open after insertion, but, with time, it became apparent there was an issue with artery reclosure (restenosis). This issue led to the development of drug-coated stents that release specially designed drugs targeted at preventing restenosis. Figure 1 shows a stent approximately 3 cm in length prior to expansion.

Figure 1 A stent before expansion.

Controlled release

The coating used for drug-eluting stents facilitates the controlled release of pharmaceuticals to ensure a specific dosage is released during a set period of time.

Controlling drug release in this way delivers drug therapy to the point at which it is most required, improving efficacy and avoiding the issue of 'human error' when it comes to self-medication. For such benefits to apply, DES coatings must release drugs in vivo according to a predictable, therapeutically rational programmed rate.

The release processes used to achieve this 'rational programmed rate' are varied; to name but a few:

• biodegradation

• diffusion (from matrix and membrane systems)

• elasticity

• conductivity

• osmosis

• pH sensitivity

• vapour pressure.

Increasingly important applications of controlled release technology also include patterned, targeted, triggered and closed-loop delivery. The question is: what can affect these systems and, subsequently, cause release variation problems? The following have all proven to be common culprits:

• variation in base material composition

• variation in base material roughness

• variation in oxide layer thickness

• variation in coating composition (i.e. drug distribution)

• variation in coating thickness.

It is essential to characterize and monitor each of these issues during initial studies to ensure the drug elution profile is correct before in vivo studies begin. This is where surface and interface analysis techniques can provide valuable analytical data. The most appropriate techniques are dynamic secondary ion mass spectrometry (DSIMS) and 3D non-contact surface profiling (3DP).

DSIMS is suitable for this particular issue because the depth profiling mode can closely monitor composition with depth. As well as identifying foreign contaminants that may be present at the very surface of a drug-eluting stent, this type of profiling also analyses the chemical composition of each layer (down to the metal substrate itself) once the stent is treated with its specific coating.

3DP complements data obtained using DSIMS and provides important information on surface parameters. These data can prove particularly useful in identifying drug release issues caused by base material roughness or coating thickness.

Common surface parameters used to analyse the surface roughness/coating thickness of drug-eluting stents are:

• S_a: arithmetic mean of the deviations from the mean. This parameter represents the mean surface roughness, measured over the whole analysed area.

• S_Z: height of the 10 points of the surface. Mean of distance between the five highest peaks and five deepest valleys. A matrix of 3×3 pixels is taken into account to identify the peaks and valleys.

• S_y: peak to peak. This parameter is a measure of the height difference between the highest pixel and the lowest pixel.

To illustrate the way these techniques and calculations are used more effectively, it is beneficial to look at a sample analysis process.

Bare metal stent analysis

The first port of call in analytical procedures designed to discover potential surface issues affecting the controlled release of pharmaceuticals from drug-eluting stents, is to examine an uncoated metal stent that has been treated only with an oxide layer. Figure 2 shows the results of this initial step using DSIMS depth profiling. Depicted in the high-depth resolution DSIMS profile are the outer 15 nm of a bare metal stent. While this particular profile reveals that the oxidization layer used to treat the bare metal stent (prior to coating application) is uniform and measures approximately 2 nm in thickness, it also reveals a distinct carbon presence (black line marked 'C').

Figure 2 Results using DSIMS depth profiling.

This reading levels out, indicating that carbon is used in the composition of the metal stent itself. However, the initial peaked reading suggests that carbon is also present at the oxide/metal interface. This could represent a contamination — one that could have an undesirable effect on subsequent pharmaceutical treatments and result in release inconsistencies.

Figure 3 shows a 2D image of an uncoated metal stent. The imaging technology can identify issues in surface topography, which may cause drug/coating distribution problems. Using data taken from various points along the sample, a mean surface roughness can be calculated. These data are particularly useful when the analysis moves on to stage two: investigating the coated stent.

Technique fact file: DSIMS

Coated stent analysis

Again, the depth profiling of DSIMS provides valuable data relating to the now multilayered stent surface — from the outer nanometres of the topcoat through to the bulk of the metal substrate.

Figure 4 shows a DSIMS depth profile of a drug-coated stent. Represented in the diagram are the polymer matrix (12C 21H), the drug (12C 14N) and the metal substrate (56Fe 16O₂₎. The profile reveals several key pieces of information when assessing potential causes of drug release issues. First, coating layer thickness can be determined by examining the concentration differences at different sample depths. This is particularly important information as erratic drug release is often caused by inconsistencies in coating thickness — thicker patches result in a slower release rate while thinner ones release the product too soon. Alternatively, patches of thinner coating could also indicate a reduced level of drug presence all together. Either way, using surface analysis of this nature quickly identifies such issues.

Technique fact file: 3DP

Returning to the information depicted in Figure 4, we see that a high concentration of drug is not present until a depth of approximately 3μm — a feature you would expect in any time-delay release mechanism. A high concentration of the drug nearer the surface may indicate an issue with drug distribution, while an unusually low drug concentration at a lower depth may reflect a problem with undesirable drug migration during storage.

No foreign contaminants are shown in this profile, but organic and inorganic contaminants (i.e., from manual handling or cleaning solvents) would also be easily identified by the depth at which they occur, giving a strong indication of where they may have been introduced in the DES or pharmaceutical coating manufacturing process.

Figure 3 3DP 2D image of an uncoated metal stent with a colour-coded thickness map.

Once again, data produced using the DSIMS depth profiling is complemented by 3DP analysis. This technique is particularly useful in analysing issues relating to drug release timings as it is the only nondestructive method of obtaining a detailed breakdown of layer thicknesses and corresponding coating distribution.

Figure 5 shows a 3DP 2D image of a drug-coated stent with a colour-coded thickness map. As polymer coatings are transparent to light, the 3DP technique can be switched from analysing surface topography to providing coating thickness values. It is possible to visually identify coating thickness and areas of uneven depth; the shallower areas perhaps indicating patches of poor drug concentration. The line shown in the diagram depicts where a line scan was taken across the stent to obtain data to calculate coating thickness.

Figure 4 DSIMS depth profile of a drug-coated stent.

Similarly, mean surface roughness can be calculated (by repeating measurements at several points along the stent) and contrasted with that of a stent prior to coating with the drug/polymer matrix. If the mean surface roughness for the coated stent is higher, it is likely to indicate a coating issue and potential inequality in drug dispersal.

Figure 5 3DP 2-dimensional image of a drug-coated stent with a colour-coded thickness map.

Analytical conclusions

Comparing just two stent samples using DSIMS and 3DP surface analysis techniques is unlikely to produce meaningful results relating to coating suitability or drug-elution properties, and a more detailed study using the above techniques would be required that incorporates a greater number of samples and includes a 'post elution' analysis. This can be achieved by 'mimicking' the body's reaction to implanted coated stents by utilizing saline buffer solutions set at 37°C (body temperature). Sample stents could then be analysed using DSIMS and 3DP at set time intervals to assess the amount of drug present and coating thicknesses at the various stages of release.

Studies of this nature will reveal key issues relating to erratic release rates, whether it is a contamination of the metal substrate or an issue with drug dispersal throughout the specific coating. With this in mind, issues with drug release timings could well benefit from the application of surface analysis techniques.

Justine Bentley joined CSMA in 2005 as a technical sales consultant. She promotes the features and benefits of surface analysis techniques to a range of sectors and disciplines, providing valuable advice on troubleshooting and on delivering analytical solutions for commercial applications, including successful product development and reverse engineering.