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Ibrutinib is the first Bruton`s tyrosine kinase (BTK) inhibitor for oral administration approved by FDA in 2014. It is the first-line treatment for B-cell malignancies, which are the most common hematologic neoplasia. Ibrutinib is a relatively safe alternative for currently used treatment modalities that are associated with long-term toxicity and resistance. However, ibrutinib is considered as BCS class II drug and has very low solubility in an aqueous medium (13 μg/ml at PH 8.0) and has six different polymorphic forms. Furthermore, recommended daily dose of ibrutinib is about 420 mg to 560 mg, which causes severe GI disturbances, with poor patient compliance. This represent a major critical concern because drug is used chronically. Increasing drug solubility and controlling rate of drug release may improve both bioavailability at significantly lower daily administered doses and by implication could minimize GI side effects and improve patient compliance.The objective of this study is to utilize Hot Melt Extrusion (HME) to develop a stable amorphous solid dispersion (ASD) of ibrutinib using Copovidone (PlasdoneTM S-630 Ultra) as a carrier for inclusion into a hydrating matrix for sustained release delivery. Development of ASD based on HME is an efficient method to overcome poor solubility problem and stabilize the drug`s metastable polymorphic states. It is known that amorphous systems are energetically at a higher thermodynamic state and can dissolve to a much greater extent relative to their crystalline counterpart. A stable sustained-release ASD based system may offer many advantages, including reduction in frequency of administration and GI disturbances with propensity to enhance solubilization while suppressing recrystallization. The ASD systems prepared in this study was stable, amorphous, and single-phase systems up to 60% API load as confirmed by X-ray powder diffraction (XRPD), modulated differential scanning calorimetry (mDSC), and rheological analysis. Supersaturated micro-dissolution testing of melt-extruded powder in fasted state simulated intestinal fluid demonstrated up to 70% increase in supersaturation solubility than the saturation solubility of crystalline counterparts. In addition, dissolution data based on the standard USP paddle method for the formulated SR tablets demonstrated a prolonged release up to six hours and a maximum of 53% higher drug release than crystalline ibrutinib. In conclusion, the results of this study indicate that ibrutinib amorphous solid dispersion developed utilizing hot-melt extrusion technology and Copovidone (PlasdoneTM S-630 Ultra) as a carrier is able to produce stable and homogeneous single-phase ASD system with enhanced solubility and desirable sustained drug release rate. / Pharmaceutical Sciences

Detta kandidatexamensarbete syftar till att finna felmoder på Scanias kopplingssystem för framtida självkörande lastbilar. Detta görs genom att fokusera på ECA (Electronic Clutch Actuator), hävarm och lager. FMEA är en riskanalys som används för att kartlägga felmoder, felorsaker och deras feleffekter. Med en 10-gradig skala görs en bedömning med avseende på tre parametrar: felsannolikhet, allvarlighetsgrad och upptäckbarhet. Ett riskprioteringstal, RPN, fås genom att multiplicera dessa. Metoder som vi använt i vår studie är ett studiebesök på SCANIA, litteraturstudier och FEM-analys av hävarmen. De sex vanligaste felmoder som identifierats för lagret är utmattning, nötning (adhesiv och abrasiv), korrosion, plastisk deformation, elektrisk korrosion och sprickbildning/brott. De vanligaste orsakerna till lagerfel kan klassificeras till områdena smörjning, montering, hantering, design och driftförhållanden. Där innefattas bl.a. främmande partiklar (smuts, nötningspartiklar), monteringsfel, linjeringsfel, otillräcklig smörjning och överbelastning. All hantering av lager är viktig då lagerfel är en kombination av flera orsaker. Enligt experter är hävarmen välkonstruerad med hög säkerhetsfaktor. Den största orsaken till fel är på grund av intilliggande komponenter som exempelvis lager och ECA. Hög temperatur ökar spänningar och deformationer väsentligt. Bristande smörjmedel i lagren vid hävarmen har identifieras som en huvudorsak till funktionsfel. Enligt experterna från reparationsverkstaden fungerar ECA enheten smidigt med väldigt lågt fel sannolikhet. / This bachelor thesis aims at finding the failure modes at Scania's clutch system for future selfdriving trucks. The examined components are the ECA (Electronic Clutch Actuator), the fork and the release bearings. The FMEA- tool was used for the mapping the failure modes, their causes and effects. This assessment is made using a 10-grade scale with respect to three parameters: occurrence, degree of severity and detectability. A risk priority number RPN, is calculated by multiplying the aforementioned numbers. The methods that we used are a study trip to SCANIA's facilities, the relevant literature on the subject, and the FEM-analyses of the fork. The six most frequent failure modes identified at the release bearing are (fatigue), wear (adhesive and abrasive), corrosion, plastic deformation, electrically induced corrosion and fractures/crack formation. The most common causes for release bearing failures are classified into smearing, assembly, handling, design and runtime circumstances. They include among others exogenous particles (dirt, wear particles), assembly errors, misalignment, insufficient (grease) and excessive loads. All handling of the release bearings is important because release bearing errors have several causes. According to experts, the clutch fork is well-designd with a high safety factor. The most common failure mode causes are a result of interactions with neighbouring components e.g. release bearing and ECA. High temperatures increase the stresses and the deformation of the components substantially. Insufficient amount of lubricant in the release bearing is identified as the main reason of failure. According to experts from the repair workshop, the ECA unit works smoothly and with a low probability of error.

Nanoparticles are important tools in biotechnology and biomedical research. Gold nanoparticles (AuNPs) have emerged as a particularly important class of nanobiotechnological tools as a result of a number of unique and useful attributes. These attributes include the high degree of biocompatibility of AuNP cores, the similarity in size of AuNPs and biomacromolecules, and the great chemical flexibility of AuNP surface design. One of the most promising applications of AuNPs in biotechnology and biomedicine is their use as drug delivery vehicles. Drug delivery vehicles provide therapeutics with desired delivery properties by targeting them specifically to the environments in which their therapeutic activity is sought and by overcoming solubility barriers. The drug delivery properties of AuNPs are a function of their sizes and surface chemistries. The nanometer scale of AuNPs allows these three-dimensional and diffusible self-assembled monolayers to act as substructures for supramolecular assemblies, to extravasate from tumor-supplying endothelia, and to undergo cellular uptake by endocytosis. AuNPs have become a versatile platform for the creation of multifunctional delivery vehicles. This work represents a collection of studies in which AuNPs have been used as probes in fundamental biological research and delivery systems for small molecules and biologics. In these studies, precision control of surface chemistry on the nanometer scale, made possible by AuNPs, has been used to find solutions to the problems of unraveling the role of hydrophobicity in immune system activation, delivering proteins past mammalian cell membranes, development of a sustained release drug delivery platform, and condensation and cellular delivery of siRNA.

An investigation into the spatial ecology and effects of catch-and-release angling on the physiology and behavior of striped bass was conducted. Fine-scale behavior was assessed by tagging fish with acoustic transmitters equipped with pressure and tri-axial accelerometer sensors and tracking them within a fixed array (n=34 receivers) in a Massachusetts estuary. Activity space changed significantly over the course of the season and increased with water temperature. Striped bass most frequently exhibited low levels of locomotory activity representing 67% of total activity measurements, with occasional high activity and burst swimming, often within the upper 3 m of the water column. Depth distribution of striped bass remained shallower when temperatures peaked at over 21 oC. Diel vertical migration was present with shallowest depths observed during the day and greatest depths during high tide. To investigate catch-and-release consequences, 102 striped bass were angled and blood sampled between July and November 2011. A subsample of 35 striped bass (July n=11, August n=11, September n=13) were implanted with tri-axial acoustic accelerometers to assess relative behavior and survival post-release. Results from principle component analyses produced five factors describing 72.7% of the variance for blood physiology parameters, total length, and water temperature. Subsequently, only eigenvalues from PC1, with high loading for blood lactate, plasma sodium and chloride, and total length, were significantly correlated with fight time. Eight individual fish were detected within 12 hours of release and exhibited their greatest mean daily activity space estimate within that time (1.5 km2 ± 0.6, 50%; 5.6 km2 ± 2.2, 95%). Depth ranged from 0-6.15 m (1.89±1.3 m) and acceleration ranged from 0.095-3.51 ms-2 (0.95±0.33). In summary, no observed mortality suggests that fish were able to recover from the physical and physiological impacts of angling. This thesis has increased the understanding of striped bass ecology and will help promote future conservation and management initiatives for striped bass and facilitate additional research.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24794号 / 医博第4986号 / 新制||医||1066(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 寺田 智祐, 教授 武藤 学, 教授 上杉 志成 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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