Volkmar Senz

Examination of drug release and distribution from drug-eluting stents with a vessel-simulating flow-through cell

The recently introduced vessel-simulating flow-through cell offers new possibilities to examine the release from drug-eluting stents in vitro. In comparison with standard dissolution methods, the additional compartment allows for the examination of distribution processes and creates dissolution conditions which simulate the physiological situation at the site of implantation. It was shown previously that these conditions have a distinct influence on the release rate from the stent coating. In this work, different preparation techniques were developed to examine the spatial distribution within the compartment simulating the vessel wall. These methods allowed for the examination of diffusion depth and the distribution resulting in the innermost layer of the compartment simulating the vessel wall. Furthermore, the in vitro release and distribution examined experimentally were modelled mathematically using finite element (FE) methods to gain further insight into the release and distribution behaviour. The FE modelling employing the experimentally determined diffusion coefficients yielded a good general description of the experimental data. The results of the modelling also provided important indications that inhomogeneous coating layer thicknesses around the strut may result from the coating process which influence release and distribution behaviour. Taken together, the vessel-simulating flow-through cell in combination with FE modelling represents a unique method to analyse drug release and distribution from drug-eluting stents in vitro with particular opportunities regarding the examination of spatial distributions within the vessel-simulating compartment.

Implant-associated local drug delivery systems based on biodegradable polymers: customized designs for different medical applications.

Abstract Implants providing controlled, local release of active substances are of interest in different medical applications. Therefore, the focus of the present article is the development of implant-associated diffusion- or chemically controlled local drug delivery (LDD) systems based on biodegradable polymeric drug carriers. In this context, we provide new data and review our own recently published data concerning the drug release behavior of diffusion-controlled LDD systems in relation to the kind of polymer, drug content, coating mass/thickness, and layer composition. We demonstrate that polymers allow a wide range of control over the drug release characteristics. In this regard, we show that the glass transition temperature of a polymer has an impact on its drug release. Additionally, the blending of hydrophobic, semicrystalline polymers with amorphous polymers leads to an increase in the rate of drug release compared with the pure semicrystalline polymer. Moreover, the percentage loading of the embedded drug has a considerable effect on the rate and duration of drug release. Furthermore, we discuss chemically controlled LDD systems designed for the release of biomolecules, such as growth factors, as well as nanoparticle-mediated LDD systems. With our own published data on drug-eluting stents, microstents, and cochlear implants, we highlight exemplary implant-associated LDD systems designed to improve implant performance through the reduction of undesirable effects such as in-stent restenosis and fibrosis.

In vitro study of sirolimus release from a drug-eluting stent: Comparison of the release profiles obtained using different test setups.

In this study drug release from the CYPHER™ stent, the gold standard in drug-eluting stent therapy until the end of its marketing in 2011/2012, was systematically evaluated using different in vitro release tests. The test systems included incubations setups, the reciprocating holder apparatus (USP7), the flow-through cell apparatus (USP4) and the vessel-simulating flow-through cell (vFTC) specifically designed for stent testing. The results obtained show a large variability regarding the fractions released into the media after 7d ranging from 38.6% ± 4.5% to 74.6% ± 1.2%. The lowest fraction released was observed in the vFTC and the highest in an incubation setup with frequently changed media of a volume of 2 mL. Differences were even observed when using fairly similar and simple incubations setups with mere changes of the media volume, under maintenance of sink conditions, and of the vessel geometry. From these data it can be concluded, that in vitro release even from a slow releasing drug-eluting stent is greatly influenced by the experimental conditions and care must be taken when choosing a suitable setup. Comparison of the obtained in vitro release profiles to published in vivo data did not result in a distinct superiority of any of the tested methods regarding the predictability for the situation in vivo due to large differences in the reported in vivo data. However, this comparison yielded that the release observed in vitro using the 2 mL incubation setup and the reciprocating holder apparatus may be faster than the reported in vivo release. The results of this study also emphasize the necessity to use highly standardized release tests when comparisons between results from different experiments or even different labs are to be performed. In this context, the compendial methods are most likely offering the highest degree of standardization.

Spray-coating process development, manufacture, quality assessment and drug release behavior of peripheral drug-eluting stents

Manufacture of peripheral DES requires development of process technologies to accommodate their geometrical and biomechanical specifics. In this study, a spray-coating process for peripheral DES coatings was developed. Peripheralsize, self-expanding nickel titanium stents (7.0 x 40 mm) were coated with the biodegradable polymer poly(L-lactide) (PLLA) incorporated with the immunosuppressant sirolimus (SIR) in a ratio of 82.5/17.5 % w/w. Coating mass was 3400 μg. A parameter study was conducted to assess optimum coating parameters. The coated DES were evaluated for coating morphology, thickness, and integrity. Drug release behavior was assessed by HPLC. SEM evaluation confirmed a smooth, defect-free PLLA/SIR coating with complete strut coverage. A coating thickness of 5.5 ± 0.4 μm was determined by CLSM. SIR release was traced over up to 430 h, exhibiting an initial burst over 30 h, followed by a steady, retarded drug release. Altogether, the results indicate the technical feasibility of self-expanding, peripheral DES.

Feasibility of Polymer/Drug Coating on Absorbable and Permanent Stent Platforms - Technological Challenges

Coating of drug-eluting stents demands different technologies depending on the nature of the stent platform, the intended coating design, and the coating materials. In this study, the complementary potentials of a spray-coating technology and a fluidized bed coating technology were assessed. Absorbable polymer stents and permanent metallic stents were coated with polymer/drug matrices based on poly(L-lactide) incorporated with the immunosuppressant sirolimus and the model substances fluorescein sodium, curcumin, and quinine. Process parameters were adjusted to yield optimal coating morphology. While spray-coating could be used to deposit even conversely asymmetric abluminal/luminal coating sandwiches, fluidized bed coating has shown tremendous throughput at a significant coating quality.

Accelerated in vitro-calcification of potential urethane based heart valve replacement materials

Abstract Polycarbonate urethane and polyether urethane nonwovens as promising representatives of novel polymer heart valve materials were analysed regarding the susceptibility to calcification in comparison to porcine pericardium and polyamide 6. The applied method represents an accelerated calcification out of a metastable solution in short time with significant precipitates on the reference material. As our results show, urethane based nonwoven structures exhibit considerably lower susceptibility to calcification compared to pericardium as widely established material for leaflet design.

Automated particle analysis by Raman microscopy – a method development

Abstract Chemical identification of particles increasingly gains importance concerning regulatory affairs of medical devices. Particle numbers of samples very easily add up to orders larger than 1.000. Therefore an automated particle measurement is absolutely worthwhile. As a method of chemical identification Raman spectroscopy combined with microscopy is commonly used. The challenge is to distinguish small particles in a range of a few microns on a surface from the background. Different specimen holder made of glass, polymer (e.g. polycarbonate) or metal are commonly used. After the choice of suitable background parameters such as magnification, optical resolution, focal plane and brightness have to be optimized. The used software for Raman microscopy offers the possibility to select particles for the subsequent measurement. Therefore the xand y-coordinates of particles have to be added to a list manually and separately. This so called point list can be processed automatically. However, this procedure is very laborious and requires a high degree of user interaction especially in case of large particle numbers. Furthermore the software offers the possibility to perform a so called area scan, where a defined surface of the the specimen will be spectroscopically analyzed. The measurements are performed in defined distances on a grid, e.g. every 10 micrometer in xand y-direction. The choice of this tool leads to a large number of measuring points associated with an unwanted long measuring time. By means of the freely accessible software ImageJ an alternative path was found to relate xand y-coordinates to every particle. These coordinates can be imported into the point list of the software for Raman microscopy. Afterwards a Raman spectrum for every particle can be measured without further high effort in time.

Investigating the Applicability of Fluidized-Bed Technology for High-Throughput Coating of Stents.

Nowadays coating of stents is associated with high manufacturing costs at least partially caused by the single unit coating process. To overcome this limitation we investigated the applicability of high-throughput stent coating via fluidized-bed technology. On the basis of an exemplary coating process we determined deviation of mass, drug release, coating homogeneity and the distribution of coating thickness of coated goods. The results indicate that the fluidizedbed technology can be utilized to obtain highly uniform stent coatings.