Herewith are presented the results of an investigation the statistical power of USP compendial release tests and recommended alternatives. <br>The U.S. drug supply chain, formerly protected by a closed distribution network, is now threatened by the legal and illegal importation of drug products. Whereas quality can never be inspected into final products, compendial release standards may represent the only valid assessment that products of dubious origin would receive. Reliable tests for content uniformity and dissolution are required to protect the safety of the supply chain. A study was designed to test the hypothesis that existing compendial tests for content uniformity and dissolution would protect the supply chain against substandard and counterfeit drugs if basic field tests failed. <br>Compendial tests for content uniformity and dissolution were evaluated for statistical power using simulation studies. The results revealed that the revised content uniformity test, based on tolerance analysis, was subject to an unacceptable level of consumers' risk. The Bergum method proved to be an excellent secondary standard for product assessment and is recommended as an alternative to the USP method. Simulations with the USP dissolution test revealed significant weaknesses and inconsistencies in the test structure. Theoretical models and power assessments confirmed that the coverage specification of the dissolution test was an unacceptably high 50% coverage with 50% confidence. <br>A Bayesian D-optimal design program was used to investigate alternative methods to improve the coverage capability of the USP dissolution test. The result of this program was the identification of two alternatives to the existing USP procedure. The first alternative is based on the addition of attribute coverage tests to stages 2 and 3 of the USP test, whereas the second alternative is based on the concept of tolerance analysis. <br>Validation studies confirmed that both alternatives significantly improved the statistical power of the USP dissolution test without increasing the sample size or modifying the current three-stage procedure. The attribute test is non-parametric and behaves similarly to the existing USP with improved coverage, whereas the continuous alternative is more sensitive and is consistent with the recent revisions to the content uniformity test. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences / Pharmaceutics / PhD / Dissertation

Reintroduction of captive-bred Western Burrowing Owls (Athene cunicularia hypugaea) in the Nicola Valley, British Columbia, has had limited success in increasing the local breeding population. Traditionally, yearling captive-hatched Burrowing Owls that were paired and released into artificial burrows in the field, held overnight, and provided with supplemental food throughout the breeding season (hard release) have had high post-release dispersal and mortality. In 2005 and 2006, I used an alternative soft-release technique to test for an improvement upon the hard-release technique. The soft release followed the same procedure as the traditional hard release but also included enclosures around burrow entrances to contain the owls for a 2-week period in the field prior to release. I compared immediate post-release dispersal, seasonal survival, and reproductive success for 37 hard-released and 30 soft-released pairs. I radio-tagged 39 of these released owls in order to accurately monitor their activities, regardless of whether they remained at release sites or dispersed. The soft-release technique led to 20% more owls remaining at the release sites, 14% more owls surviving the breeding season, and 20% more owl pairs fledging juveniles. In addition to investigating adult survival and reproductive success, I examined post-fledging juvenile survival, local recruitment, and habitat use, and adult prey consumption behaviour in order to assess the potential of these aspects to limit the success of the reintroduction. Survival and local recruitment rates of the juveniles of captive-bred adults released with two different techniques were similar to that of juveniles of wild adults in the same study area or in other parts of the Burrowing Owl's range. Juvenile habitat-selection analyse sidentified the importance of rangeland, and comparisons of prey consumption revealed the rapid development of foraging abilities by captive-bred Burrowing Owls. I concluded that these aspects of the owl's ecology were not negatively affected by a captive upbringing, and therefore not likely limiting the success of the reintroduction. Overall, the use of an enclosure-based soft-release technique addresses major limitations to the success of releases, and shows promise for increasing the breeding population in this region. This approach can also be applied to recovery efforts throughout the Burrowing Owls' range, and provide guidelines for other species' reintroduction programs.

Typically the combustion in engines are open-loop controlled. By using an in-cylinder pressure sensor it is possible to create virtual sensors for closed-loop combustion control (CLCC). With CLCC it is possible to counteract dynamic effects as component ageing, fuel type and cylinder variance. A virtual sensor system was implemented based on a one-zone heat-release analysis, including signal processing of the pressure sensor input. A parametrisation of the heat-release based on several Vibe functions was implemented with good results. The major focus of the virtual sensor system was to perform a tolerance analysis on experimental data, where typical error sources in a production heavy-duty vehicle were identified and their effect on the estimates quantified. It could be concluded that estimates are very much dependent on the choice of heat-release and specific heat ratio models. Especially crank angle phasing has a large impact on estimation performance, stressing the importance of accounting for crankshaft torsion in production vehicles. Biodiesel advances the combustion angle and give a lower IMEP and total heat amount compared to standard diesel. However, error sensitivity is not affected. Further investigations must be made on improving the signal processing in terms of gain error compensation and filtering. Also a better understanding of how errors propagate between subsystems in a CLCC system is required for successful implementation.

Neste trabalho os retornos de ativos financeiros são modelados com base em dados não-estruturados de notícias aperiódicas. O cerne do tratamento de tais dados está na Recuperação da Informação, que se importa em aplicar uma transformação suficientemente representativa das estruturas de contexto gramatical para o algébrico. Trabalhos anteriores mostram que não só o timing (GOODHART, HALL, et al., 1993), tipo (ÄIJÖ, 2008), ou contexto no momento de publicação da notícia (BEBER e BRANDT, 2010), mas também o conteúdo léxico (WÜTHRICH, PERMUNETILLEKE, et al., 1998; LAVRENKO, SCHMILL, et al., 2000; SCHUMAKER e CHEN, 2009) explicam movimentos de mercado. Este trabalho tem por objetivo estender a discussão já fundamentada sobre a semântica das publicações, com a proposta de aprofundar a avaliação da sensibilidade paramétrica do ajuste de modelos já encontrados na literatura. Questões sobre a metodologia de pré-processamento dos textos são exploradas por meio de diversos experimentos. Por fim, corrobora-se os resultados prévios sobre a possibilidade de aplicar-se uma classificação preditiva sobre movimentos do mercado acionário norte-americano, particularmente dentro da janela de 15 a 25 minutos após a publicação de um press release. Contudo, não são encontradas evidências com de que regressão tenha a mesma capacidade, nem de que exista antecipação pelo mercado da informação a ser anunciada. / In this paper the returns of financial assets are modeled based on data from unstructured aperiodic news. The core processing of such data in is information retrieval, which deals with applying a transformation sufficiently representative from structures of grammatical to algebraic contexts. Previous works show that not only the news timing (GOODHART, HALL, et al., 1993), its type (ÄIJÖ, 2008), or its context in the moment of announcement (BEBER e BRANDT, 2010), but also its lexical content (WÜTHRICH, PERMUNETILLEKE, et al., 1998; LAVRENKO, SCHMILL, et al., 2000; SCHUMAKER e CHEN, 2009) explain movements on the market. This work aims to extend the ongoing discussion over the semantics of publications, with the proposal of further evaluating the sensitivity of the model\'s parametric fitting found in the literature. Questions raised about the methodology of pre-processing of texts are explored through various experiments. Finally, previous results on the possibility of applying a predictive classification of the U.S. stock market movements are corroborated, particularly inside a time frame from 15 to 25 minutes after the publication of a press release. However, no evidence is found with ? <= 0.01 that regression has the same capacity, nor that there is anticipation of market information to be announced.

Reintroduction of captive-bred Western Burrowing Owls (Athene cunicularia hypugaea) in the Nicola Valley, British Columbia, has had limited success in increasing the local breeding population. Traditionally, yearling captive-hatched Burrowing Owls that were paired and released into artificial burrows in the field, held overnight, and provided with supplemental food throughout the breeding season (hard release) have had high post-release dispersal and mortality. In 2005 and 2006, I used an alternative soft-release technique to test for an improvement upon the hard-release technique. The soft release followed the same procedure as the traditional hard release but also included enclosures around burrow entrances to contain the owls for a 2-week period in the field prior to release. I compared immediate post-release dispersal, seasonal survival, and reproductive success for 37 hard-released and 30 soft-released pairs. I radio-tagged 39 of these released owls in order to accurately monitor their activities, regardless of whether they remained at release sites or dispersed. The soft-release technique led to 20% more owls remaining at the release sites, 14% more owls surviving the breeding season, and 20% more owl pairs fledging juveniles. In addition to investigating adult survival and reproductive success, I examined post-fledging juvenile survival, local recruitment, and habitat use, and adult prey consumption behaviour in order to assess the potential of these aspects to limit the success of the reintroduction. Survival and local recruitment rates of the juveniles of captive-bred adults released with two different techniques were similar to that of juveniles of wild adults in the same study area or in other parts of the Burrowing Owl's range. Juvenile habitat-selection analyse sidentified the importance of rangeland, and comparisons of prey consumption revealed the rapid development of foraging abilities by captive-bred Burrowing Owls. I concluded that these aspects of the owl's ecology were not negatively affected by a captive upbringing, and therefore not likely limiting the success of the reintroduction. Overall, the use of an enclosure-based soft-release technique addresses major limitations to the success of releases, and shows promise for increasing the breeding population in this region. This approach can also be applied to recovery efforts throughout the Burrowing Owls' range, and provide guidelines for other species' reintroduction programs. / Land and Food Systems, Faculty of / Graduate

The topical application of many substances, including drugs, enzymes, moisturizers and fragrances, contributes largely to the cosmetic and pharmaceutical industries. These components are often volatile in nature and dissipate in a matter of hours. When considering the different types of slow release systems, an overwhelming variety of these systems is available. Each one of the systems is unique in a way, and is designed to perform a particular function, whether it facilitates the controlled release of an active into the body via the skin surface (transdermal delivery) or whether it reduces the rate of loss of an active from the skin surface to the surrounding environment. For the purpose of this study, a previously existing fixative formulation which is believed to reduce the rate of loss of an active component to the environment, through film formation on the skin surface, was investigated. Alternative ingredients or components were incorporated together with the original fixative formulation ingredients into an experimental design which investigates the effect of each group of the components present. 18 formulations with various concentrations of the components within the groups and specified upper and lower limits for each component were formulated. The fixative properties of the formulations were analysed through the incorporation of a fixed amount of a simple fragrance molecule, 4- methoxybenzaldehyde, into each formulation and evaporation studies were conducted in an environmental room at 28±1° C over a period of 5 hours followed by gas chromatography analysis and finally data analyses using statistical methods. The most efficient fixative formulation was established using regression analysis. The fragrance compound in this formulation was found to evaporate at a rate of 0.47 g/L per hour. The least efficient fixative formulation lead to the loss of 0.78 g/L of the fragrance component per hour. From the calculated fragrance concentrations, the rate constant for each individual fixative formulation could be calculated and response surface 8 modelling by backward regression was used in order to determine how each component contributes to the rate of loss of the fragrance compound. Since the sum of the original ingredient and its alternative was constant, each of the original ingredients was coupled directly to its alternative and no conclusion could be made about the contribution of individual components. By increasing the concentration of Hydroxypropylcellulose (HPC) 100K and its alternative HPC 140K, while keeping the effects of the other components constant, a decrease in the rate of fragrance loss was observed. The same conclusion could be made when increasing the concentrations of PEG-12 Dimethicone and its alternative cetyl dimethicone (decreases the evaporation rate). An interaction took place between HPC 100K and PEG-12 dimethicone and their alternatives. The negative effect was, however, not as strong as the combined positive effect on the rate of fragrance loss of the individual components HPC and PEG-12 dimethicone. Evidence suggested that the removal of the components polyvinylpyrrolidone and its alternative, polyurethane-32 (Baycusan® C1003), would improve the effectiveness of the fixative formulation in terms of its slow release properties. A confirmation experiment established that the exclusion of these components from the fixative formulation does improve the “slow release” properties thereof. A larger, more intricate design is required to investigate the effect of each one of the individual components and where the sum of the components (original and its alternative) is not constant.

Tissue response to PNIPAM and HPC nanoparticles has been studied by implantation method. The results suggest that both PNIAPM and HPC nanoparticles possess good biocompatibility and they may serve as a good carrier for the applications of controlled delivery. Rheological properties of dispersions of IPN microgels composed of PNIPAM and PAAc have been studied. It is found that the IPN microgel dispersion can undergo a sol-gel transition at temperature above 33°C. In vivo drug release experiments suggest that the gelation procedure creates a diffusion barrier and thus leads to slow release. An emulsion method has been used to grow columnar crystals by mixing PNIPAM microgel dispersions with organic solvents. Effect of both temperature and microgel concentration on formation of columnar crystals has been studied. PNIPAM-co-NMA microgels have been used for the fabrication of crystalline hydrogel films by self-crosslinking microgels. The hydrogel film exhibits an iridescent. The thermally responsive properties and mechanical properties of this film have been studied. Melting temperature (Tm) of colloidal crystals self-assembled with PNIPAM-co-AAc microgels has been investigated as a function of pH, salt concentration and microgel concentration. It is revealed that Tm increases as pH value increases; Tm decreases with increase of salt concentration; Tm increases as microgel concentration increases. Phase behavior of PNIPAM-co-HEAc microgel dispersions has been investigated. It is observed that these microgel dispersions exhibit liquid, crystal, and glass phase. As microgel size increases, crystal phase shifts to low concentration range. As temperature increases, crystal phase shifts to high concentration ranges. These colloidal crystals can be stabilized by NaOH-induced gelation. Effect of NaOH concentration on formation of physical gelation has been investigated.

<p>As amorphous solid dispersions (ASDs) are more widely employed as a formulation strategy for poorly water-soluble drugs, there is a pressing need to increase the drug loading in these formulations. The drug loading is typically kept low to obtain the desired drug release rate, but often results in large or even multiple dosage units, which is undesirable from a patient compliance perspective. We have identified the cause of this conundrum to be the drug loading dependent dissolution mechanism of ASDs. At low drug loadings, the dissolution rate of ASDs is polymer-controlled, while at high drug loadings, the dissolution rate is drug-controlled and considerably slower. This phenomenon is most pronounced for ASDs with hydrophilic polymers, such as poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA) and the change in dissolution mechanism from being polymer-controlled to drug-controlled has been attributed to water-induced amorphous-amorphous phase separation (AAPS) in higher drug loading ASD matrices of hydrophilic polymers. The drug loading limit for this switch has been found to be dependent on drug properties as well as drug-polymer interactions. Interestingly, drug-polymer hydrogen bonding interaction has been found to be detrimental and decrease the drug loading limit for polymer-controlled release while drug log P did not have any impact on this limit. Variable dissolution temperature studies indicated a detrimental impact on the polymer-controlled drug loading limit when the drug-rich phase (of phase separated ASD matrix) exists in a glassy state. ASDs with relatively hydrophobic polymers, such as hypromellose acetate succinate (HPMCAS), have been found to be polymer-controlled up to higher drug loadings. The mechanistic understanding obtained in this body of work can thus be adopted to develop strategies enabling ASD formulations with optimized performance and improved drug loading.</p>

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18133号 / 医博第3853号 / 新制||医||1001(附属図書館) / 30991 / 京都大学大学院医学研究科医学専攻 / (主査)教授 坂田 隆造, 教授 瀬原 淳子, 教授 開 祐司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・論文博士 / 博士(農学) / 乙第13100号 / 論農博第2846号 / 新制||農||1051(附属図書館) / 学位論文||H29||N5032(農学部図書室) / (主査)教授 松村 康生, 教授 裏出 令子, 教授 谷 史人 / 学位規則第4条第2項該当 / Doctor of Agricultural Science / Kyoto University / DFAM