Polymeereillä stabiloitu amorfinen formulaatio

Nowadays growing number of new active pharmaceutical ingredients (API) have large molecular weight and are hydrophobic. The energy of their crystal lattice is bigger and polarity has decreased. This leads to weakened solubility and dissolution rate of the drug. These properties can be enhanced for example by amorphization. Amorphous form has the best dissolution rate in the solid state. In the amorphous form drug molecules are randomly arranged, so the energy required to dissolve molecules is lower compared to the crystalline counterpart. The disadvantage of amorphous form is that it is unstable. Amorphous form tends to crystallize. Stability of amorphous form can be enhanced by adding an adjuvant to drug product. Adjuvant is usually a polymer. Polymers prevent crystallization both by forming bonds with API molecules and by steric hindrance. The key thing in stabilizing amorphous form is good miscibility between API and polymer. They have to be mixed in a molecular level so that the polymer is able to prevent crystallization. The aim of this work was to study miscibility of drug and polymer and stability of their dispersion with different analytical methods. Amorphous dispersions were made by rotary evaporator and freeze dryer. Amorphicity was confirmed with X-ray powder diffraction (XRPD) right after preparation. Itraconazole and theophylline were the chosen molecules to be stabilized. Itraconazole was expected to be easier and theophylline more difficult to stabilize. Itraconazole was stabilized with HPMC and theophylline was stabilized with PVP. Miscibility was studied with XRPD and differential scanning calorimetry (DSC). In addition it was studied with polarized light microscope if miscibility was possible to see visually. Dispersions were kept in stressed conditions and the crystallization was analyzed with XRPD. Stability was also examined with isothermal microcalorimetry (IMC). The dispersion of itraconazole and theophylline 40/60 (w/w) was completely miscible. It was proved by linear combination of XRPD results and single glass transition temperature in DSC. Homogenic well mixed film was observed with light microscope. Phase separation was observed with other compositions. Dispersions of theophylline and PVP mixed only partly. Stability of itraconazole dispersions were better than theophylline dispersions which were mixed poorer. So miscibility was important thing considering stability. The results from isothermal microcalorimetry were similar to results from conventional stability studies. Complementary analytical methods should be used when studying miscibility so that the results are more reliable. Light microscope is one method in addition to mostly used XRPD and DSC. Analyzing light microscope photos is quite subjective but it gives an idea of miscibility. Isothermal microcalorimetry can be one option for conventional stability studies. If right conditions can be made where the crystallization is not too fast, it may be possible to predict stability with isothermal microcalorimetry.

Lyophilized disaccharides – the effect of water during storage

Nearly one fourth of new medicinal molecules are biopharmaceutical (protein, antibody or nucleic acid derivative) based. However, the administration of these compounds is not always that straightforward due to the fragile nature of aforementioned domains in GI-tract. In addition, these molecules often exhibit poor bioavailability when administered orally. As a result, parenteral administration is commonly preferred. In addition, shelf-life of these molecules in aqueous environments is poor, unless stored in low temperatures. Another approach is to bring these molecules to anhydrous form via lyophilization resulting in enhanced stability during storage. Proteins cannot most commonly be freeze dried by themselves so some kind of excipients are nearly always necessary. Disaccharides are commonly utilized excipients in freeze-dried formulations since they provide a rigid glassy matrix to maintain the native conformation of the protein domain. They also act as "sink"-agents, which basically mean that they can absorb some moisture from the environment and still help to protect the API itself to retain its activity and therefore offer a way to robust formulation. The aim of the present study was to investigate how four amorphous disaccharides (cellobiose, melibiose, sucrose and trehalose) behave when they are brought to different relative humidity levels. At first, solutions of each disaccharide were prepared, filled into scintillation vials and freeze dried. Initial information on how the moisture induced transformations take place, the lyophilized amorphous disaccharide cakes were placed in vacuum desiccators containing different relative humidity levels for defined period, after which selected analyzing methods were utilized to further examine the occurred transformations. Affinity to crystallization, water sorption of the disaccharides, the effect of moisture on glass transition and crystallization temperature were studied. In addition FT-IR microscopy was utilized to map the moisture distribution on a piece of lyophilized cake. Observations made during the experiments backed up the data mentioned in a previous study: melibiose and trehalose were shown to be superior over sucrose and cellobiose what comes to the ability to withstand elevated humidity and temperature, and to avoid crystallization with pharmaceutically relevant moisture contents. The difference was made evident with every utilized analyzing method. In addition, melibiose showed interesting anomalies during DVS runs, which were absent with other amorphous disaccharides. Particularly fascinating was the observation made with polarized light microscope, which revealed a possible small-scale crystallization that cannot be observed with XRPD. As a result, a suggestion can safely be made that a robust formulation is most likely obtained by utilizing either melibiose or trehalose as a stabilizing agent for biopharmaceutical freeze-dried formulations. On the other hand, more experiments should be conducted to obtain more accurate information on why these disaccharides have better tolerance for elevating humidities than others.

Two views on interstellar dust: near-infrared scattering and polarized thermal dust emission

Interstellar clouds are not featureless, but show quite complex internal structures of filaments and clumps when observed with high enough resolution. These structures have been generated by 1) turbulent motions driven mainly by supernovae, 2) magnetic fields working on the ions and, through neutral-ion collisions, on neutral gas as well, and 3) self-gravity pulling a dense clump together to form a new star. The study of the cloud structure gives us information on the relative importance of each of these mechanisms, and helps us to gain a better understanding of the details of the star formation process. Interstellar dust is often used as a tracer for the interstellar gas which forms the bulk of the interstellar matter. Some of the methods that are used to derive the column density are summarized in this thesis. A new method, which uses the scattered light to map the column density in large fields with high spatial resolution, is introduced. This thesis also takes a look at the grain alignment with respect to the magnetic fields. The aligned grains give rise to the polarization of starlight and dust emission, thus revealing the magnetic field. The alignment mechanisms have been debated for the last half century. The strongest candidate at present is the radiative torques mechanism. In the first four papers included in this thesis, the scattered light method of column density estimation is formulated, tested in simulations, and finally used to obtain a column density map from observations. They demonstrate that the scattered light method is a very useful and reliable tool in column density estimation, and is able to provide higher resolution than the near-infrared color excess method. These two methods are complementary. The derived column density maps are also used to gain information on the dust emissivity within the observed cloud. The two final papers present simulations of polarized thermal dust emission assuming that the alignment happens by the radiative torques mechanism. We show that the radiative torques can explain the observed decline of the polarization degree towards dense cores. Furthermore, the results indicate that the dense cores themselves might not contribute significantly to the polarized signal, and hence one needs to be careful when interpreting the observations and deriving the magnetic field.

The Reorganisation of Provincial Territories in Light of the Imperial Decision-Making Process : Later Roman Arabia and Tres Palaestinae as Case Studies

The dissertation examines Roman provincial administration and the phenomenon of territorial reorganisations of provinces during the Imperial period with special emphasis on the provinces of Arabia and Palaestina during the Later Roman period, i.e., from Diocletian (r. 284 305) to the accession of Phocas (602), in the light of imperial decision-making. Provinces were the basic unit of Roman rule, for centuries the only level of administration that existed between the emperor and the cities of the Empire. The significance of the territorial reorganisations that the provinces were subjected to during the Imperial period is thus of special interest. The approach to the phenomenon is threefold: firstly, attention is paid to the nature and constraints of the Roman system of provincial administration. Secondly, the phenomenon of territorial reorganisations is analysed on the macro-scale, and thirdly, a case study concerning the reorganisations of the provinces of Arabia and Palaestina is conducted. The study of the mechanisms of decision-making provides a foundation through which the collected data of all known major territorial reorganisations is interpreted. The data concerning reorganisations is also subjected to qualitative comparative analysis that provides a new perspective to the data in the form of statistical analysis that is sensitive to the complexities of individual cases. This analysis of imperial decision-making is based on a timeframe stretching from Augustus (r. 30 BC AD 14) to the accession of Phocas (602). The study identifies five distinct phases in the use of territorial reorganisations of the provinces. From Diocletian s reign there is a clear normative change that made territorial reorganisations a regular tool of administration for the decision-making elite for addressing a wide variety of qualitatively different concerns. From the beginning of the fifth century the use of territorial reorganisations rapidly diminishes. The two primary reasons for the decline in the use of reorganisations were the solidification of ecclesiastical power and interests connected to the extent of provinces, and the decline of the dioceses. The case study of Palaestina and Arabia identifies seven different territorial reorganisations from Diocletian to Phocas. Their existence not only testifies to wider imperial policies, but also shows sensitivity to local conditions and corresponds with the general picture of provincial reorganisations. The territorial reorganisations of the provinces reflect the proactive control of the Roman decision-making elite. The importance of reorganisations should be recognised more clearly as part of the normal imperial administration of the provinces and especially reflecting the functioning of dioceses.

Luke, The Friend of Sinners

I examine the portrayal of Jesus as a friend of toll collectors and sinners in the Third Gospel. I aim at a comprehensive view on the Lukan sinner texts, combining questions of the origin and development of these texts with the questions of Luke s theological message, of how the text functions as literature, and of the social-historical setting(s) behind the texts. Within New Testament scholarship researchers on the historical Jesus mostly still hold that a special mission to toll collectors and sinners was central in Jesus public activity. Within Lukan studies, M. Goulder, J. Kiilunen and D. Neale have claimed that this picture is due to Luke s theological vision and the liberties he took as an author. Their view is disputed by other Lukan scholars. I discuss methods which scholars have used to isolate the typical language of Luke s alleged written sources, or to argue for the source-free creation by Luke himself. I claim that the analysis of Luke s language does not help us to the origin of the Lukan pericopes. I examine the possibility of free creativity on Luke s part in the light of the invention technique used in ancient historiography. Invention was an essential part of all ancient historical writing and therefore quite probably Luke used it, too. Possibly Luke had access to special traditions, but the nature of oral tradition does not allow reconstruction. I analyze Luke 5:1-11; 5:27-32; 7:36-50; 15:1-32; 18:9-14; 19:1-10; 23:39-43. In most of these some underlying special tradition is possible though far from certain. It becomes evident that Luke s reshaping was so thorough that the pericopes as they now stand are decidedly Lukan creations. This is indicated by the characteristic Lukan story-telling style as well as by the strongly unified Lukan theology of the pericopes. Luke s sinners and Pharisees do not fit in the social-historical context of Jesus day. The story-world is one of polarized right and wrong. That Jesus is the Christ, representative of God, is an intrinsic part of the story-world. Luke wrote a theological drama inspired by tradition. He persuaded his audience to identify as (repenting) sinners. Luke's motive was that he saw the sinners in Jesus' company as forerunners of Gentile Christianity.

Agreeable Agreement : An Examination into the Quest for a Solid Consensus in Light of Bilateral Doctrinal Dialogues among Anglicans, Lutherans and Roman Catholics

The purpose of this study is to analyse the development and understanding of the idea of consensus in bilateral dialogues among Anglicans, Lutherans and Roman Catholics. The source material consists of representative dialogue documents from the international, regional and national dialogues from the 1960s until 2006. In general, the dialogue documents argue for agreement/consensus based on commonality or compatibility. Each of the three dialogue processes has specific characteristics and formulates its argument in a unique way. The Lutheran-Roman Catholic dialogue has a particular interest in hermeneutical questions. In the early phases, the documents endeavoured to describe the interpretative principles that would allow the churches to together proclaim the Gospel and to identify the foundation on which the agreement in the church is based. This investigation ended up proposing a notion of basic consensus , which later developed into a form of consensus that seeks to embrace, not to dismiss differences (so-called differentiated consensus ). The Lutheran-Roman Catholic agreement is based on a perspectival understanding of doctrine. The Anglican-Roman Catholic dialogue emphasises the correctness of interpretations. The documents consciously look towards a common future , not the separated past. The dialogue s primary interpretative concept is koinonia. The texts develop a hermeneutics of authoritative teaching that has been described as the rule of communion . The Anglican-Lutheran dialogue is characterised by an instrumental understanding of doctrine. Doctrinal agreement is facilitated by the ideas of coherence, continuity and substantial emphasis in doctrine. The Anglican-Lutheran dialogue proposes a form of sufficient consensus that considers a wide set of doctrinal statements and liturgical practices to determine whether an agreement has been reached to the degree that, although not complete , is sufficient for concrete steps towards unity. Chapter V discusses the current challenges of consensus as an ecumenically viable concept. In this part, I argue that the acceptability of consensus as an ecumenical goal is based not only the understanding of the church but more importantly on the understanding of the nature and function of the doctrine. The understanding of doctrine has undergone significant changes during the time of the ecumenical dialogues. The major shift has been from a modern paradigm towards a postmodern paradigm. I conclude with proposals towards a way to construct a form of consensus that would survive philosophical criticism, would be theologically valid and ecumenically acceptable.

Spectral Tuning and Adaptation to Different Light Environments of Mysid Visual Pigments

In the present thesis, questions of spectral tuning, the relation of spectral and thermal properties of visual pigments, and evolutionary adaptation to different light environments were addressed using a group of small crustaceans of the genus Mysis as a model. The study was based on microspectrophotometric measurements of visual pigment absorbance spectra, electrophysiological measurements of spectral sensitivities of dark-adapted eyes, and sequencing of the opsin gene retrieved through PCR. The spectral properties were related to the spectral transmission of the respective light environments, as well as to the phylogentic histories of the species. The photoactivation energy (Ea) was estimated from temperature effects on spectral sensitivity in the long-wavelength range, and calculations were made for optimal quantum catch and optimal signal-to-noise ratio in the different light environments. The opsin amino acid sequences of spectrally characterized individuals were compared to find candidate residues for spectral tuning. The general purpose was to clarify to what extent and on what time scale adaptive evolution has driven the functional properties of (mysid) visual pigments towards optimal performance in different light environments. An ultimate goal was to find the molecular mechanisms underlying the spectral tuning and to understand the balance between evolutionary adaptation and molecular constraints. The totally consistent segregation of absorption maxima (λmax) into (shorter-wavelength) marine and (longer-wavelength) freshwater populations suggests that truly adaptive evolution is involved in tuning the visual pigment for optimal performance, driven by selection for high absolute visual sensitivity. On the other hand, the similarity in λmax and opsin sequence between several populations of freshwater M. relicta in spectrally different lakes highlights the limits to adaptation set by evolutionary history and time. A strong inverse correlation between Ea and λmax was found among all visual pigments studied in these respects, including those of M. relicta and 10 species of vertebrate pigments, and this was used to infer thermal noise. The conceptual signal-to-noise ratios thus calculated for pigments with different λmax in the Baltic Sea and Lake Pääjärvi light environments supported the notion that spectral adaptation works towards maximizing the signal-to-noise ratio rather than quantum catch as such. Judged by the shape of absorbance spectra, the visual pigments of all populations of M. relicta and M. salemaai used exclusively the A2 chromophore (3, 4-dehydroretinal). A comparison of amino acid substitutions between M. relicta and M. salemaai indicated that mysid shrimps have a small number of readily available tuning sites to shift between a shorter - and a longer -wavelength opsin. However, phylogenetic history seems to have prevented marine M. relicta from converting back to the (presumably) ancestral opsin form, and thus the more recent reinvention of marine spectral sensitivity has been accomplished by some other novel mechanism, yet to be found

Molecular Tuning of Rhodopsins for High Visual Sensitivity in Different Light Environments : Variation in Absorbance Spectrum and Opsin Sequence within and between Species

Visual pigments of different animal species must have evolved at some stage to match the prevailing light environments, since all visual functions depend on their ability to absorb available photons and transduce the event into a reliable neural signal. There is a large literature on correlation between the light environment and spectral sensitivity between different fish species. However, little work has been done on evolutionary adaptation between separated populations within species. More generally, little is known about the rate of evolutionary adaptation to changing spectral environments. The objective of this thesis is to illuminate the constraints under which the evolutionary tuning of visual pigments works as evident in: scope, tempo, available molecular routes, and signal/noise trade-offs. Aquatic environments offer Nature s own laboratories for research on visual pigment properties, as naturally occurring light environments offer an enormous range of variation in both spectral composition and intensity. The present thesis focuses on the visual pigments that serve dim-light vision in two groups of model species, teleost fishes and mysid crustaceans. The geographical emphasis is in the brackish Baltic Sea area with its well-known postglacial isolation history and its aquatic fauna of both marine and fresh-water origin. The absorbance spectrum of the (single) dim-light visual pigment were recorded by microspectrophotometry (MSP) in single rods of 26 fish species and single rhabdoms of 8 opossum shrimp populations of the genus Mysis inhabiting marine, brackish or freshwater environments. Additionally, spectral sensitivity was determined from six Mysis populations by electroretinogram (ERG) recording. The rod opsin gene was sequenced in individuals of four allopatric populations of the sand goby (Pomatoschistus minutus). Rod opsins of two other goby species were investigated as outgroups for comparison. Rod absorbance spectra of the Baltic subspecies or populations of the primarily marine species herring (Clupea harengus membras), sand goby (P. minutus), and flounder (Platichthys flesus) were long-wavelength-shifted compared to their marine populations. The spectral shifts are consistent with adaptation for improved quantum catch (QC) as well as improved signal-to-noise ratio (SNR) of vision in the Baltic light environment. Since the chromophore of the pigment was pure A1 in all cases, this has apparently been achieved by evolutionary tuning of the opsin visual pigment. By contrast, no opsin-based differences were evident between lake and sea populations of species of fresh-water origin, which can tune their pigment by varying chromophore ratios. A more detailed analysis of differences in absorbance spectra and opsin sequence between and within populations was conducted using the sand goby as model species. Four allopatric populations from the Baltic Sea (B), Swedish west coast (S), English Channel (E), and Adriatic Sea (A) were examined. Rod absorbance spectra, characterized by the wavelength of maximum absorbance (λmax), differed between populations and correlated with differences in the spectral light transmission of the respective water bodies. The greatest λmax shift as well as the greatest opsin sequence difference was between the Baltic and the Adriatic populations. The significant within-population variation of the Baltic λmax values (506-511 nm) was analyzed on the level of individuals and was shown to correlate well with opsin sequence substitutions. The sequences of individuals with λmax at shorter wavelengths were identical to that of the Swedish population, whereas those with λmax at longer wavelengths additionally had substitution F261F/Y in the sixth transmembrane helix of the protein. This substitution (Y261) was also present in the Baltic common gobies and is known to redshift spectra. The tuning mechanism of the long-wavelength type Baltic sand gobies is assumed to be the co-expression of F261 and Y261 in all rods to produce ≈ 5 nm redshift. The polymorphism of the Baltic sand goby population possibly indicates ambiguous selection pressures in the Baltic Sea. The visual pigments of all lake populations of the opossum shrimp (Mysis relicta) were red-shifted by 25 nm compared with all Baltic Sea populations. This is calculated to confer a significant advantage in both QC and SNR in many humus-rich lakes with reddish water. Since only A2 chromophore was present, the differences obviously reflect evolutionary tuning of the visual protein, the opsin. The changes have occurred within the ca. 9000 years that the lakes have been isolated from the Sea after the most recent glaciation. At present, it seems that the mechanism explaining the spectral differences between lake and sea populations is not an amino acid substitution at any other conventional tuning site, but the mechanism is yet to be found.

The effect of exercise and light on mood

The aim of the study was to compare the effect physical exercise and bright light has on mood in healthy, working-age subjects with varying degrees of depressive symptoms. Previous research suggests that exercise may have beneficial effects on mood at least in subjects with depression. Bright light exposure is an effective treatment of winter depression, and possibly of non-seasonal depression as well. Limited data exist on the effect of exercise and bright light on mood in non-clinical populations, and no research has been done on the combination of these interventions. Working-age subjects were recruited through occupational health centres and 244 subjects were randomized into intervention groups: exercise, either in bright light or normal lighting, and relaxation / stretching sessions, either in bright light or normal gym lighting. During the eight-week intervention in midwinter, subjects rated their mood using a self-rating version of the Hamilton Depression Scale with additional questions for atypical depressive symptoms. The main finding of the study was that both exercise and bright-light exposure were effective in treating depressive symptoms. When the interventions were combined, the relative reduction in the Hamilton Depression Scale was 40 to 66%, and in atypical depressive symptoms even higher, 45 to 85%. Bright light exposure was more effective than exercise in treating atypical depressive symptoms. No single factor could be found that would predict a good response to these interventions. In conclusion, aerobic physical exercise twice a week during wintertime was effective in treating depressive symptoms. Adding bright light exposure to exercise increased the benefit, especially by reducing atypical depressive symptoms. Since this is so, this treatment could prevent subsequent major depressive episodes among the population generally.

Search for a Light Higgs Boson in Central Exclusive Diffraction: Method and Detectors

By detecting leading protons produced in the Central Exclusive Diffractive process, p+p → p+X+p, one can measure the missing mass, and scan for possible new particle states such as the Higgs boson. This process augments - in a model independent way - the standard methods for new particle searches at the Large Hadron Collider (LHC) and will allow detailed analyses of the produced central system, such as the spin-parity properties of the Higgs boson. The exclusive central diffractive process makes possible precision studies of gluons at the LHC and complements the physics scenarios foreseen at the next e+e− linear collider. This thesis first presents the conclusions of the first systematic analysis of the expected precision measurement of the leading proton momentum and the accuracy of the reconstructed missing mass. In this initial analysis, the scattered protons are tracked along the LHC beam line and the uncertainties expected in beam transport and detection of the scattered leading protons are accounted for. The main focus of the thesis is in developing the necessary radiation hard precision detector technology for coping with the extremely demanding experimental environment of the LHC. This will be achieved by using a 3D silicon detector design, which in addition to the radiation hardness of up to 5×10^15 neutrons/cm2, offers properties such as a high signal-to- noise ratio, fast signal response to radiation and sensitivity close to the very edge of the detector. This work reports on the development of a novel semi-3D detector design that simplifies the 3D fabrication process, but conserves the necessary properties of the 3D detector design required in the LHC and in other imaging applications.

Characterizing Physical Properties of Wetting Paper by Air Coupled Ultrasound and Light

This thesis reports investigations into the paper wetting process and its effects on the surface roughness and the out-of-plane (ZD) stiffness of machine-made paper. The aim of this work was to test the feasibility of employing air-borne ultrasound methods to determine surface roughness (by reflection) and ZD stiffness (by through transmission) of paper during penetration of distilled water, isopropanol and their mixtures. Air-borne ultrasound provides a non-contacting way to evaluate sample structure and mechanics during the liquid penetration event. Contrary to liquid immersion techniques, an air-borne measurement allows studying partial wetting of paper. In addition, two optical methods were developed to reveal the liquid location in paper during wetting. The laser light through transmission method was developed to monitor the liquid location in partially wetted paper. The white light reflection method was primarily used to monitor the penetration of the liquid front in the thickness direction. In the latter experiment the paper was fully wetted. The main results of the thesis were: 1) Liquid penetration induced surface roughening was quantified by monitoring the ultrasound reflection from the paper surface. 2) Liquid penetration induced stiffness alteration in the ZD of paper could be followed by measuring the change in the ultrasound ZD resonance in paper. 3) Through transmitted light revealed the liquid location in the partially wetted paper. 4) Liquid movement in the ZD of the paper could be observed by light reflection. The results imply that the presented ultrasonic means can without contact measure the alteration of paper roughness and stiffness during liquid transport. These methods can help avoiding over engineering the paper which reduces raw material and energy consumption in paper manufacturing. The presented optical means can estimate paper specific wetting properties, such as liquid penetration speed, transport mechanisms and liquid location within the paper structure. In process monitoring, these methods allow process tuning and manufacturing of paper with engineered liquid transport characteristics. With such knowledge the paper behaviour during printing can be predicted. These findings provide new methods for paper printing, surface sizing, and paper coating research.