Mesoporous silica- and silicon-based materials as carriers for poorly water soluble drugs

New chemical entities with unfavorable water solubility properties are continuously emerging in drug discovery. Without pharmaceutical manipulations inefficient concentrations of these drugs in the systemic circulation are probable. Typically, in order to be absorbed from the gastrointestinal tract, the drug has to be dissolved. Several methods have been developed to improve the dissolution of poorly soluble drugs. In this study, the applicability of different types of mesoporous (pore diameters between 2 and 50 nm) silicon- and silica-based materials as pharmaceutical carriers for poorly water soluble drugs was evaluated. Thermally oxidized and carbonized mesoporous silicon materials, ordered mesoporous silicas MCM-41 and SBA-15, and non-treated mesoporous silicon and silica gel were assessed in the experiments. The characteristic properties of these materials are the narrow pore diameters and the large surface areas up to over 900 m²/g. Loading of poorly water soluble drugs into these pores restricts their crystallization, and thus, improves drug dissolution from the materials as compared to the bulk drug molecules. In addition, the wide surface area provides possibilities for interactions between the loaded substance and the carrier particle, allowing the stabilization of the system. Ibuprofen, indomethacin and furosemide were selected as poorly soluble model drugs in this study. Their solubilities are strongly pH-dependent and the poorest (< 100 µg/ml) at low pH values. The pharmaceutical performance of the studied materials was evaluated by several methods. In this work, drug loading was performed successfully using rotavapor and fluid bed equipment in a larger scale and in a more efficient manner than with the commonly used immersion methods. It was shown that several carrier particle properties, in particular the pore diameter, affect the loading efficiency (typically ~25-40 w-%) and the release rate of the drug from the mesoporous carriers. A wide pore diameter provided easier loading and faster release of the drug. The ordering and length of the pores also affected the efficiency of the drug diffusion. However, these properties can also compensate the effects of each other. The surface treatment of porous silicon was important in stabilizing the system, as the non-treated mesoporous silicon was easily oxidized at room temperature. Different surface chemical treatments changed the hydrophilicity of the porous silicon materials and also the potential interactions between the loaded drug and the particle, which further affected the drug release properties. In all of the studies, it was demonstrated that loading into mesoporous silicon and silica materials improved the dissolution of the poorly soluble drugs as compared to the corresponding bulk compounds (e.g. after 30 min ~2-7 times more drug was dissolved depending on the materials). The release profile of the loaded substances remained similar also after 3 months of storage at 30°C/56% RH. The thermally carbonized mesoporous silicon did not compromise the Caco-2 monolayer integrity in the permeation studies and improved drug permeability was observed. The loaded mesoporous silica materials were also successfully compressed into tablets without compromising their characteristic structural and drug releasing properties. The results of this research indicated that mesoporous silicon/silica-based materials are promising materials to improve the dissolution of poorly water soluble drugs. Their feasibility in pharmaceutical laboratory scale processes was also confirmed in this thesis.

Computer simulation of multi-elemental fusion reactor materials

Thermonuclear fusion is a sustainable energy solution, in which energy is produced using similar processes as in the sun. In this technology hydrogen isotopes are fused to gain energy and consequently to produce electricity. In a fusion reactor hydrogen isotopes are confined by magnetic fields as ionized gas, the plasma. Since the core plasma is millions of degrees hot, there are special needs for the plasma-facing materials. Moreover, in the plasma the fusion of hydrogen isotopes leads to the production of high energetic neutrons which sets demanding abilities for the structural materials of the reactor. This thesis investigates the irradiation response of materials to be used in future fusion reactors. Interactions of the plasma with the reactor wall leads to the removal of surface atoms, migration of them, and formation of co-deposited layers such as tungsten carbide. Sputtering of tungsten carbide and deuterium trapping in tungsten carbide was investigated in this thesis. As the second topic the primary interaction of the neutrons in the structural material steel was examined. As model materials for steel iron chromium and iron nickel were used. This study was performed theoretically by the means of computer simulations on the atomic level. In contrast to previous studies in the field, in which simulations were limited to pure elements, in this work more complex materials were used, i.e. they were multi-elemental including two or more atom species. The results of this thesis are in the microscale. One of the results is a catalogue of atom species, which were removed from tungsten carbide by the plasma. Another result is e.g. the atomic distributions of defects in iron chromium caused by the energetic neutrons. These microscopic results are used in data bases for multiscale modelling of fusion reactor materials, which has the aim to explain the macroscopic degradation in the materials. This thesis is therefore a relevant contribution to investigate the connection of microscopic and macroscopic radiation effects, which is one objective in fusion reactor materials research.

Kansan raittiudeksi ja kotien onneksi : Naisten kieltolakimielipiteet ja toiminta kieltolain puolesta ja sitä vastaan 1919 - 1932

It is often maintained that the Prohibition Act (in force from 1 June 1919 to 5 April 1932) still influences both the Finnish alcohol policy and notions about alcohol. This study focuses on the development of women s opinions concerning Prohibition in Finland. What role did the formulation and expression of women s opinions and women's actions play in the final outcome of the Prohibition Act? What do the debate on Prohibition and women s activities for and against the legislation tell us about the status and possibilities of women to exert influence in the Finnish society of the Prohibition era? Women s opinions are particularly interesting since they deviated radically from what has generally been assumed. It was expected that the referendum of 1931 would result in a resounding vote of 100% in favour of Prohibition, but the outcome was a majority vote against it. Over 65% of the women who cast their vote in the referendum wanted a full repeal of Prohibition. The study approaches the history of Prohibition by combining methods and theories of the history of mentalities and social history with gender history. Women are examined as a heterogeneous group with dissimilar objectives and differing ways of acting and thinking. The research material consists of press materials, archival materials from organisations, personal materials and statistics from the Prohibition period. Both discourses and practices are examined; the object of the research is best described by Michel Foucault's concept of dispositif. When participating in the public debate on Prohibition, women based their right to express their opinions and take part in action on an ideological continuum spanning a hundred years, according to which home and family were central areas of women s interest. This idea was linked to questions of morality and social policy. On the other hand, women presented themselves as working taxpayers, voters and equal citizens. The most crucial issue in women's discussions was whether Prohibition improved or worsened the temperance of fathers, husbands and sons. The dichotomies town dweller - countryside dweller, Swedish-speaking Finnish-speaking, and middle class - working class were highly significant backgrounds both as factors dividing women and in public discussions regarding Prohibition. The 1931 referendum showed that the lines of demarcation drawn during the preceding debate did not materialise in political action in line with these dichotomies: the dispositif did not correspond to the discourse. Contrary to what was expressed in public, a great number of women among the labour and rural classes, among inland inhabitants and among Finnish-speakers were also against Prohibition. The media and organisations defended temperance and Prohibition almost until the end of the Prohibition era. This discourse was in conflict with the discourse of everyday conversations and practices in which alcohol was present.