The aim of this dissertation is to investigate and optimize the preparation of steroid loaded particles, to increase drug loading by enhanced polymer-drug interactions, and the surfactant free stabilization of nanoparticles in the dry state. Different particle preparation methods are described and advantages and drawbacks are discussed. As sample molecules for drug loading, budesonide and estradiol are explored.
In chapter II, the versatile properties of nano- and microparticles are introduced and the advantages of nanoparticulate drug delivery to the lungs are elucidated. Especially, efficient and preservative delivery of nanoobjects to specific regions of the lungs is focused. Local pulmonary and systemic diseases are depicted and potential treatment by polymeric nanoparticles is presented. Nanoparticle preparations for small molecular drug delivery are discussed as well as for protein and peptides or nucleonic acids.
In chapter III, loading of a corticosteroid hormone, budesonide, into particles is investigated. Drawbacks and opportunities of different preparation methods on drug loading of steroids in poly(lactide-co-glycolide) particles are illustrated. Nanoparticles dispersed in water are prepared by two fundamental different methods: “solvent displacement” and “solvent emulsion”. Drug loading and release are determined as key characteristics of the particles gained. Microparticles are prepared for comparison by spray-drying and a more sophisticated method, electro spraying. The aim of this chapter is to select preparation parameters enhancing drug loading and prolonged release for a combination of drug and polymer.
In contrast, the chapter IV deals with the optimization of polymer properties to increase drug loading for estradiol, another steroid hormone. Cyclodextrins can form inclusion complexes with small molecules and increase drug solubility. Introduction of β-cyclodextrins in the polymer matrix are expected to increased drug-polymer interactions. Different core molecules are grafted with PLGA. The synthesized polymers are analyzed by size exclusion chromatography, differential scanning calorimetry, nuclear magnetic resonance spectroscopy and tested for hemolytic activity. Nanoparticles are prepared by “solvent displacement” and characterized regarding to size, drug loading and drug release in comparison to particles of cyclodextrin-polymer blends. The scope of this study is to investigate if drug loading efficacy for PLGA-nanoparticles can be increased by optimization of the polymer matrix by introduction of cyclodextrin binding sites.
Finally, prepared nanoparticles are stabilized in chapter V. Stabilization in dry state is difficult for nanoobjects; high surface energy forces the particles to aggregation. The selection of appropriate spacer molecules is intended to reduce aggregation forces. Spray-drying is selected as the method of choice, since it is well established in drug manufacturing, and continuous fabrication is possible. Additionally, the application of suitable preparation conditions enables the microparticles to be used directly as transport vehicles for pulmonary delivery. Surface active substances can irritate the sensitive endothelia in the lungs, so that surfactants should be avoided. The aim of this investigation was to establish surfactant free microcarriers for the transport of redispersible nanoparticles.
Chapter VI presents a short summary and gives some perspectives of this work.