Polyurethane membrane with porous surface for controlled drug release in drug eluting stent
© Seo and Na; licensee BioMed Central Ltd. 2014
Received: 30 July 2014
Accepted: 24 September 2014
Published: 8 October 2014
Membrane covered drug eluting stents (DES) were prepared to prevent tumor ingrowth and to control drug release. Polyurethane (PU) is commonly used for DES coating material because of high tensile strength. The release of paclitaxel (PTX) may increase from porous PU membrane.
Polyethylene glycol (PEG) was incorporated into PU membranes to form porous structure and control the release of hydrophobic anti-cancer drug such as PTX. The bare metal stents were coated with PEG incorporated PU and then, PEG was washed out to form porous structure. The crystallization of PTX was inhibited in porous PU membranes and the release of PTX from porous PU membranes was approximately 8.6% more extended over 19 days.
The enhanced release of PTX from porous PU membranes may increase the patency for the DES covering materials.
Most cancers of extrahepatic bile ducts cause biliary obstruction . The insertion of a bare metal stent is a widely used technique for patients with this malignancy, because this technique prolongs survival, shortens hospital stay, and improves quality of life . However, these stents also have disadvantages of occlusion over time because of tumor ingrowth or overgrowth , and mucosal hyperplasia as a consequence of chronic irritation. Moreover, bare metal stents merely promote biliary drainage and have no antitumor effect .
Alternatively the local drug delivery system via a stent that is covered with an antitumor-drug-releasing membrane makes it possible to treat a target tissue without adverse systemic effects . The bare metal stent that is covered with paclitaxel (PTX) incorporated membrane that has an antineoplastic effect has been developed . Previously, a polyurethane (PU) membrane was prepared for potential applications to stent-based drug delivery and the local treatment of malignant tumors around non-vascular stents . The PU membrane generally has a high tensile strength that is physically useful as a covering material for gastrointestinal stents that should be compressed inside an introducer tube with a minimum volume during the delivery to the obstructed lumen . Based on the upper reasons, the PU membrane was developed and applied using a dip coating method  as part of a PTX-loaded controlled-release membrane for drug-eluting non-vascular stents.
However, the release of PTX was inversely proportional to the PTX loading. This type of the smaller drug release rate with the higher drug loading was reported by S. G. Kang group  investigated the percentage of PTX released from PU membrane decreased with the increase in PTX loading. They reported this inverse-relationship of cumulative release % with drug loading is expected, since the amount of drug released from the PU membranes was virtually independent of the drug loading.
Polyethylene glycol (PEG) are commonly incorporated as a pore forming agent to enhance the release of hydrophobic drugs . PEG was incorporated in PU and washed out from PU membranes to form porous structure [12, 13]. The increased surface area of porous structure can facilitate a hydrophobic drug release rate even though higher drug loading . Therefore, we assumed that the porous PU membrane using PEG has possibility to enhance the release of PTX from drug eluting stents (DES).
In this study, the influence of porous structure in the PTX incorporated PU membrane was investigated. Also, the surface morphology and pore size were determined by SEM and drug release behavior was confirmed.
Polyurethane (PU, Pellethane 2363-80AE, Lubrizol) and bare metal stents were supplied by Teawoong medical co. Ltd. (Kimpo-si, South Korea). Polyethylene glycol (PEG, average Mn 2,050), tert-butyl methyl ether (tBME), tween 20 was purchased from Sigma Aldrich (St.Louis, MO, USA) and tetrahydrofuran (THF) was purchased from Junsei chemical (Tokyo, Japan). Paclitaxel (PTX) was purchased from Samyang biopharmaceuticals (Seoul, South Korea). All of the other chemicals and solvents were analytical grade.
Preparation of PU membranes and PU coated bare metal stents
Composition of PU solution and thickness of PU membranes
Membrane type (w/w%)
Membrane thickness (μm)a
Characterization of PU membranes
Thickness of PU membranes was measured by micro-meter caliper (Mitutoyo, Japan). Surface and cross-sectioned morphology of PU membranes and PU coated bare metal stents were observe with field emission-scanning electron microscopy (FE-SEM, Hitachi S-4800, Tokyo, Japan). The membranes and stents were sliced into small pieces (1 cm × 1 cm), mounted on carbon tape, sputter coated with platinum using an ion coater (10 mA, 45 sec), and then observed at an accelerating voltage of 10 kV.
In vitroPTX release test
PTX (50 mg) was added into 10 mL of PU solution containing various amount of PEG. PTX loaded porous PU membrane was fabricated by above-mentioned method. To investigate drug release profile, approximately 0.46 mg/cm2 of PTX incorporated porous and non-porous PU membranes were fabricated. The membranes were placed into 15 mL conical tubes, and 10 mL of 0.1% of tween 20 containing 0.01 M phosphate-buffered saline solution (PBST) was added (n = 3). Release test was performed in shaking water bath at 37°C and 50 rpm for 19 days. The PBST in each tube was collected and replaced at specified times. The released PTX was extracted into tBME. The tBME was completely evaporated at room temperature for overnight and re-dissolved in 200 μL of HPLC grade methanol (Honeywell-Burdick and Jackson). The released PTX was quantified by high performance liquid chromatography (HPLC) equipped with ultraviolet (UV) detector at 227 nm at a flow rate of 1.0 mL/min with HPLC grade methanol as the mobile phase at room temperature . The column was C18 reverse phase column (Thermo Scientific). The HPLC was calibrated with PTX standard solutions of 1 to 100 μg/mL (correlation coefficient R 2 = 0.998).
Results and discussion
Characterization of PU membranes
PU membrane stent cover depending on PEG concentration
In vitroPTX release test
PTX-incorporated PU membranes
Membrane type (w/w%)
PTX amounts (mg/cm2)
In this study, we investigated the effect of porous PU membrane as a bare metal stent coating material. The porous structure was formed by washing out of PEG from PU membranes. The release of PTX from porous PU membranes was increased for 19 days. This porous PU membrane could inhibit PTX crystallization and increase drug release because porous structure had larger surface area. The enhanced release of drug from porous PU membranes increases the potential usefulness of a bare metal stent cover to limited drug release of hydrophobic anti-cancer drug, PTX.
This work was supported by the Technology Innovation Program (10044021, Development of nonvascular drug eluting stent for treatment of gastrointestinal disease) funded by Ministry of Trade, industry & Energy (MOTIE, Korea).
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