Publikationsserver der Universitätsbibliothek Marburg

Titel:Spray drying for the preparation of innovative nanocoatings and inhalable nanocarriers
Autor:Baghdan, Elias
Weitere Beteiligte: Bakowsky, Udo (Prof. Dr.)
URN: urn:nbn:de:hebis:04-z2018-05222
DDC: Pharmakologie, Therapeutik
Titel (trans.):Sprühtrocknung für die Herstellung innovativer Nanobeschichtungen und inhalierbarer nanoskaliger Wirkstoffträger


Sprühtrocknung, nanoskalige Wirkstoffträger, Spray drying, nanoparticles, coating, Beschichtung

Spray drying is a well-established method for the transformation of liquid formulations into dried particles. This technique is still gaining increasing interest due to its numerous advantages and wide range of applications. Furthermore, the emergence of nano spray drying in the last decade, took the capabilities of spray drying to the next level, especially in the field of nanoparticle production. This thesis comprises detailed studies on the applications of spray drying in two important fields: pulmonary drug delivery and coating of medical implants. The first objective was to employ spray drying in developing an inhalable photosensitizer loaded formulation for the bronchoscopic photodynamic therapy. Pulmonary administration of photosensitizers will help achieving both selective and completely non-invasive treatment against lung cancer. Thus, offering a promising alternative to the intravenous route and achieving better patient compliance. Curcumin was chosen as a naturally occurring photosensitizer; however, its low water solubility and poor bioavailability were the main drawbacks. Therefore, curcumin nanoparticles were prepared using the nanoprecipitation method to enhance its efficacy against tumor cells. According to dynamic light scattering measurements, curcumin nanoparticles had a homogenous size distribution and a particle size suitable for cellular uptake. The prepared nanoparticles exhibited a good hemocompatibility with minor hemolytic potential and no critical influence on coagulation time. In vitro irradiation experiments using human lung epithelial carcinoma cells (A549) revealed an effective photoresponse of curcumin nanoparticles as they were able to destroy cancer cells upon activation with a light of specific wavelength using LED irradiating device. Moreover, curcumin nanoparticles exhibited a dose-dependent photocytotoxicity and the IC50 values of curcumin were directly dependent on the radiation fluence used. Nano-in-Microparticles were produced by spray drying curcumin nanoparticles with mannitol, thereby transforming the nanoparticles into a dry powder for inhalation without experiencing drastic conditions. The aerodynamic properties of the Nano-in-Microparticles were investigated using the next generation impactor which revealed a large fine particle fraction and an appropriate mass median aerodynamic diameter for a sufficient deposition in the lungs. The Nano-in-Microparticles exhibited a good redispersibility and disintegrated into the original nanoparticles upon redispersion in aqueous medium. This can be attributed to mannitol which was used as the wall material embedding the nanoparticles to keep them intact during the drying process and facilitate their release from the microparticles. Langmuir monolayer experiments confirmed the compatibility of the Nano-in-Microparticles with the pulmonary surfactant which is an important prerequisite for the safe delivery of curcumin to its site of action in the lungs (i.e. tumor cells). These results demonstrated the feasibility of spray drying for preparing inhalable drug carriers with promising potentials in the field of photodynamic therapy. In vivo studies should be the next step in order to evaluate the ability of these formulations to overcome the biological barriers of the lung. Furthermore, an accurate dosage assessment must be performed to achieve an effective therapy. The second objective was to introduce nano spray drying as a novel technique for the preparation of nanoparticles of different biomaterials that are capable of modifying the surface structure of medical implants even those with a challenging topography. The Nano Spray Dryer B-90 with its unique advanced features, facilitated particles production and implant coating in a single step omitting the need of additional drying or washing steps. This newly developed coating technique will offer several advantages: a) the ability to produce particles in the submicron range from the pure substance solution without any additives (e.g. surfactants) or time-consuming complex modifications; b) very gentle process conditions that are suitable even for sensitive and thermolabile substances (e.g. enzymes, hormones and nucleic acids); c) this technique is highly efficient and cost-effective, since a small amount of the sample is needed to achieve the best results; d) the unique cylindrical shape and functional principle of the particle collector enable a stable spatial surface coating, making upscaling easily applicable since it is possible to fix several implants on the particle collector to be coated simultaneously. In this thesis, the wide range applicability of this coating technique has been demonstrated by testing three representative model substances, namely chitosan, poly(lactic-co-glycolic acid) and curcumin. Preliminary experiments were performed on titanium plates to optimize the process parameters, thereby achieving small particle size, narrow size distribution and complete coverage of the implants. The optimized parameters were thereafter successfully applied on dental implants and the coating homogeneity was confirmed using fluorescence microscopy. Scanning electron microscope images showed that most of the produced particles were in the submicron range and had a spherical shape with a smooth surface. Particle size analysis indicated the influence of the implant position inside the particle collector on the particle size distribution where the bottom part of the collector had the particles with the narrowest size distribution. These findings paved the way for preparing biocompatible nanocoatings with antibacterial activity. The optimized process parameters from the preliminary experiments were applied on titanium discs, which were used as a model material for dental implants. The produced nanocoatings consisted of poly(lactic-co-glycolic acid) as a biodegradable polymer and norfloxacin as a model antibiotic. Scanning electron microscopy results of the nanocoatings were similar to those of preliminary experiments in terms of particle size distribution, morphology and surface structure which confirmed the reproducibility of this coating technique. The nanocoatings exhibited a typical biphasic drug release profile with a burst release in the first 48 h, followed by sustained release phase until the end of experiment. Antibacterial activity of the nanocoatings was evaluated against Escherichia coli in two stages: first, qualitatively, using agar diffusion test which facilitated the examination of large number of samples, and then quantitatively, by counting the number of viable bacterial colonies adhered to the surface of the titanium discs. The antibacterial activity of the norfloxacin loaded nanocoatings was evident and could be observed either as zone of inhibitions (agar diffusion test) or as a significant reduction in the number of viable bacterial colonies (quantification experiments). This activity was directly dependent on the norfloxacin content in the nanocoatings which was influenced by the theoretical norfloxacin loading and the titanium disc position inside the particle collector. Finally, in vitro biocompatibility of the nanocoatings was investigated using mouse fibroblasts (L929) as a standard sensitive cell line for cytotoxicity assessment. Cell proliferation on the surface of the titanium discs was studied using fluorescence microscopy followed by cell counting assay. Both methods confirmed the biocompatibility of the examined nanocoatings which exhibited similar results when compared to the uncoated titanium discs. Although nano spray drying has shown such interesting potentials for preparing novel nanocoatings, there is still room for improvement. This coating technique is still at its infancy and further optimization of the process parameters seems to be essential in order to produce nanocoatings capable of improving cell adhesion and exhibiting potent antibacterial activity even without the need of antibacterial agent.

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