No abstract

Polymeric microspheres have gained widespread application as drug eluting depots. Typically, drug-loaded polymeric microspheres are prepared by oil-in-water emulsification which yields a product with a broad size distribution. The aim of the present study was to investigate the properties of different size-fractions of drug-loaded microspheres, in order to delineate whether particle size governs drug loading efficiency and release profile. Gefitinib-loaded PLGA-based microspheres were prepared using an oil-in-water solvent evaporation method and wet-sieved to obtain well-defined size fractions of 5 ± 1, 32 ± 4, 70 ± 3, and 130 ± 7 μm, respectively. The average drug loading of unfractionated microspheres was 6.3 ± 0.4% w/w, while drug loading of sieved fractions ranged from 2.4 ± 0.3 to 7.6 ± 0.9% w/w for smallest to largest microparticles. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analysis demonstrated that gefitinib was amorphously dispersed in the PLGA matrix, with no apparent shift in the T of PLGA indicating the absence of direct molecular interactions of the drug and polymer due to the formation of small drug particles embedded in PLGA. In vitro drug release was studied with microspheres embedded in dextran hydrogels to avoid their aggregation during the incubation conditions. Microspheres smaller than 50 μm showed rapid diffusion-based release reaching completion within 2 days when particles have not degraded yet. Larger microspheres, however, showed a sigmoidal release pattern that continued for three months in which diffusion (early stage) as well as particle erosion (later stage) governed drug release. Scanning electron microscopy (SEM) and polymer degradation data showed that larger microspheres degraded faster than smaller ones, which is in line with autocatalytic PLGA degradation upon acidification within the core of microparticles. In conclusion, we showed that different size-fractions of drug-loaded microspheres showed quite distinct drug loading and release kinetics. Control of microparticle size by fractionation is therefore an important determinant for obtaining well-defined and reproducible sustained release depots.

Clinical evaluations have proven the efficacy of drug-elution stents (DES) in reduction of in-stent restenosis rates as compared to drug-free bare metal stents (BMS). Typically, DES are metal stents that are covered with a polymer film loaded with anti-inflammatory or antiproliferative drugs that are released in a sustained manner. However, although favorable effects of the released drugs have been observed, the polymer coating as such has been associated with several adverse clinical effects, such as late stent thrombosis. Elimination of the polymeric carrier of DES may therefore potentially lead to safer DES. Several technologies have been developed to design polymer-free DES, such as the use of microporous stents and inorganic coatings that can be drug loaded. Several drugs, including sirolimus, tacrolimus, paclitaxel, and probucol have been used in the design of carrier-free stents. Due to the function of the polymeric coating to control the release kinetics of a drug, polymer-free stents are expected to have a faster drug elution rate, which may affect the therapeutic efficacy. However, several polymer-free stents have shown similar efficacy and safety as the first-generation DES, although the superiority of polymer-free DES has not been established in clinical trials.

One of the complications of bronchotracheal cancer is obstruction of the upper airways. Local tumor resection in combination with an airway stent can suppress intraluminal tumor (re)growth. We have investigated a novel drug-eluting stent coating for local release of the anticancer drug gefitinib. A polyurethane (PU) sandwich construct was prepared by a spray coating method in which gefitinib was embedded between a PU support layer of 200 μm and a PU top layer of 50-200 μm. Gefitinib was either embedded in the construct as small crystals or as gefitinib-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres (MSP). The drug was incorporated in the PU constructs with high recovery (83-93%), and the spray coating procedure did not affect the morphologies of the embedded microspheres as demonstrated by scanning electron microscopy (SEM), confocal laser scanning microscopy and fluorescence microscopy analysis. PU constructs loaded with gefitinib crystals released the drug for 7-21 days and showed diffusion based release kinetics. Importantly, directional release of the drug towards the top layer, which is supposed to face the tumor mass, was controlled by the thicknesses of the PU top layer. PU constructs loaded with gefitinib microspheres released the drug in a sustained manner for N 6 months indicating that drug release from the microspheres became the rate limiting step. In conclusion, the sandwich structure of drug-loaded PLGA microspheres in PU coating is a promising coating for airway stents that release anticancer drugs locally for a prolonged time.

The purpose of the present study was to develop gefitinib-loaded polymeric foams that can be used as coating of drug-eluting stents for palliative treatment of bronchotracheal cancer. Release of such an anticancer drug from such stent coating can retard tumor regrowth into the bronchial lumen. Gefitinib-loaded polyurethane (PU) foams were prepared by embedding either gefitinib micronized crystals or gefitinib-loaded poly(lactic-co-glycolic acid) microspheres in water-blown films, with up to 10% w/w loading for gefitinib microcrystals and 15% w/w for gefitinib microspheres (corresponding to 1.0% w/w drug loading). Drug-release studies showed sustained release of gefitinib over a period of nine months, with higher absolute release rates at higher drug loading content. By the end of the studied nine month release periods, 60-100% of the loaded gefitinib had been released. Foams loaded with gefitinib-PLGA microspheres at 15% w/w showed accelerated drug release after 4 months, coinciding with the degradation of PLGA microparticles in the PU foam as demonstrated by scanning electron microscopy (SEM). When applied on a nitinol braided bronchotrachial stent, PU coatings with gefitinib microspheres showed similar mechanical properties as the drug-free PU coating, which indicated that the loading of microspheres did not affect the mechnical properties of the PU foams. In conclusion, we have fabricated drug-loaded PU foams that are suitable for bronchotracheal stent coating.