Дисертації з теми "Delayed releases"

Afin d'améliorer la prédiction de possibles relâchements tardifs de radionucléides lors d'un accident grave d'un réacteur nucléaire, les phénomènes de remobilisation de dépôt de Produits de Fission (PF) dans le circuit primaire sont étudiés. Ces phénomènes induisent un changement d'état des PF ou une réactivité chimique contribuent à la formation d'espèces gazeuses ou d'aérosols en suspension dans le flux de gaz, contribuant aux rejets atmosphériques. Ce travail, dans le cadre du projet OCDE ESTER, se concentre sur la revaporisation du césium (Cs) et de l'iode (I) en tant que principaux contributeurs aux conséquences radiologiques d'un accident grave. De plus, le tellure (Te) qui peut être une source d'I par désintégration radioactive est également étudié. Pour ce faire, deux méthodologies complémentaires sont utilisées :- Des expérimentations de revaporisation visent à évaluer le taux de revaporisation de chaque élément étudié, d'identifier les espèces revaporisées et de caractériser les espèces solides restantes.- Des simulations à l'équilibre thermodynamique visent à définir les principales réactions de revaporisation et la spéciation des espèces transportées.Différents simulants de dépôts de PF dans le circuit primaire ont été considérés : CsI, CsOH, CdI2, H2TeO4 et TeO2. Grâce au dispositif expérimental ATMIRE couvrant une large gamme de températures (de 200 à 600 °C), une large gamme de pressions partielles d'air (de 4.5.10-4 à 0.5 atm) complétée par de la vapeur d'eau et des vapeurs de bore dans le gaz porteur, la revaporisation de source de Cs, I , et Te a été étudiée. Les échantillons ont été caractérisés grâce à la combinaison d'analyses chimiques et de surfaces telles que ICP-MS, l'XPS et le ToF-SIMS. Grâce à ces techniques, l'identification et la quantification des espèces gazeuses et solides formées tout au long des essais ont été possibles. Par la suite, les résultats expérimentaux ont été comparés aux calculs à l'équilibre thermodynamique pour confirmer les principales voies de revaporisation de chaque simulant de PF.Au-dessus de 400 °C, la revaporisation du CsI entraîne à la fois sa vaporisation et sa décomposition sous atmosphère air/vapeur. La décomposition de CsI conduit à la formation d'iode gazeux (HOI, I ou I2) et d'espèces Cs telles que CsOH et CsNO3 ainsi que Cs2CrO4 (en raison de l'interaction du Cs avec l'acier oxydé) ou CsBO2 (par interaction avec le bore dans l'atmosphère de revaporisation).Sous atmosphère vapeur/air, le CdI2 est totalement décomposé au-dessus de 200 °C, entraînant la formation d'I gazeux (principalement I2) et de Cd (tel que CdO ou Cd(OH)2).Enfin, à haute température (supérieure à 400 °C), H2TeO4 est réduit et déshydraté pour former TeO2 quelle que soit la proportion d'air dans l'atmosphère (de 4.5.10-4 atm à 1 atm). Pour TeO2, la revaporisation n'est pas influencée par la proportion d'air mais est fortement augmentée en présence de CsOH avec la formation d'espèces de type Cs-Te-O (tel que Cs2TeO3 ou Cs2TeO4)
In order to improve the prediction of possible delayed radioactive releases during a SA of a PWR, remobilization phenomena of Fission Product (FP) deposited in the Reactor Cooling System (RCS) have been investigated. These phenomena induce a modification of the FP state to gaseous species or aerosols suspended in the gas flow contributing to these delayed releases. This work, within the OECD ESTER project, is focusing on the revaporization of Cs and I as main contributors to radiological consequences. In addition, tellurium (Te) which may be a source of I by radioactive decay is also studied. To do so, two complementary methodologies are used:- Revaporization experiments aim at assessing the revaporization rate of each studied element, at identifying the revaporized species, and finally at characterizing the remaining solid species.- Thermodynamic simulations aim at defining the main revaporization reactions and the airborne species.Different simulants for FP deposits in the RCS were considered: CsI, CsOH, CdI2, H2TeO4 TeO2. Thanks to the ATMIRE experimental setup covering a large range of temperatures (from 200 to 600 °C), a large range of air partial pressures (from 4.5.10-4 to 0.5 atm) complemented by steam boron vapors in the carrier gas, revaporization behaviors of Cs, I, Cd and Te were characterized. The samples were characterized thanks to combined chemical and surface analyses such as ICP-MS, XPS, and ToF-SIMS. Thanks to these techniques, identification and quantification of both gaseous and solid species formed throughout the tests were possible. Then experimental results were compared to thermodynamic calculations to confirm the main revaporization paths of each FP simulant.Above 400 °C, the CsI revaporization result in both CsI vaporization and decomposition under an air/steam atmosphere. CsI decomposition leads to the formation of gaseous iodine (HOI, I, or I2) and Cs species such as CsOH and CsNO3 as well as Cs2CrO4 (due to Cs interaction with oxidized SS) or CsBO2 (by interaction with boron in the revaporization atmosphere).Under steam/air atmosphere, CdI2 is totally decomposed above 200 °C leading to the formation of gaseous I (mainly I2) and Cd (such as CdO or Cd(OH)2).Finally, at high temperatures (above 400 °C), H2TeO4 is reduced and dehydrated to form TeO2 whatever the proportion of air (from 4.5.10-4 atm to 1 atm). For TeO2, revaporization is not influenced by Pair but is strongly increased in presence of CsOH with the formation of Cs-Te-O species (such as Cs2TeO3 or Cs2TeO4)

A rational approach was adopted in the design of a novel controlled release system aimed at delivering hydrophobic drugs in a wholly time-dependent manner. A swellable, rupturable system in which hydrophobic drugs were solubilised in vegetable oils was proposed. Two main components of the system, the swelling agent low-substituted hydroxypropylcellulose (grade LH-21) and brittle outer coating of ethylcellulose (EC) were individually characterised. Upon contact with water, LH-21 swelled rapidly and to a great extent, exemplified by using simple apparatus to measure water uptake and swelling force. Mixing it with other excipients such as vegetable oils, surfactants and drugs tended to decrease LH-21 water uptake rate and subsequent force generation rate. Solution-cast EC films enabled thorough investigations into the mechanical integrity and physicochemical properties of the proposed outer coating of the capsule. Plasticisation decreased the strength while increasing the malleability of the film while increasing polymer content toughened the film and increased its elastic modulus. These findings were extrapolated to the construction of the dosage form in its two configurations. The first involved filling a hard gelatin capsule with a dispersion of LH-21 in corn oil and coating it with EC. In the second, a gelatin-based tablet separated LH-21 and corn oil. Burst release following a lag time was obtained with both configurations. In general, decreasing the LH-21 concentration and increasing the EC coating level prolonged the lag time. A limit of LH-21 concentration was identified below which more sustained release was observed indicating sufficient LH-21 was required to efficiently expel the capsule fill. Problems with leakage of the oil component were addressed in the hope of manufacturing reproducible dosage forms. Improvements to the construction process are essential if successful drug delivery is to be achieved.

The mentally ill who have been found not guilty of a crime by reason of insanity (NGRI), appear to be at risk in several areas when confronted with the judicial system. The purpose of this study is to determine whether the factors which predict recidivism of NGRI patients in Community Out-patient Treatment (COT) also inhibit a patient's release into a conditional release program (CONREP).

Modified-release oral drug delivery dosage forms are widely used in the pharmaceutical field to overcome all the potential issues imposed by the physiological variabilities of the gastrointestinal tract as well as to maintain drug concentrations within the therapeutic window. In the market, they are available only as solid dosage forms such as capsules or tablets. The development of a liquid oral dosage form with modified-release properties has been keenly awaited. This form could increase the compliance of patients with a swallowing impairment (i.e. paediatric, older or critically ill patients) and, consequently, the efficacy of the therapeutic treatment. In this study, a new technology has been developed that consists of multi-layered particles suspended extemporaneously in a syrup. Omeprazole and budesonide have been employed as model drugs. The coating procedure was optimized to obtain a yield of minimum 90% w/w and a median diameter below 500 µm. Once the final suspension is prepared extemporaneously, it presents sufficient stability to guarantee the administration of multiple doses filled into a syrup bottle and kept for a limited storage time at room temperature (e.g. up to 10 doses to be administered within 10 days).
Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie)
info:eu-repo/semantics/nonPublished

A dynamic model is developed for the purpose of predicting stability characteristics of an industrial-scale, swirl-stabilized premixed combustor located at the National Energy Technology Laboratory (NETL) in Morgantown, WV. The model consists of modular blocks that assemble into an open-loop transfer function depicting the frequency response of the thermoacoustic system. These blocks include the system acoustic response to unsteady heat release forcing, the air-side coupling of acoustic particle velocity to inlet fuel mass fraction, transport delays present in the mixing nozzle and combustion chamber, and dynamic heat release excitation from unsteady inlet fuel mass fraction. By examing the frequency response with linear stability techniques, the existence of limit cycles due to linear instabilities is predicted. Further, the frequency response analysis is used to predict limit cycle frequencies in the case of predicted instability. The analysis predictions are compared with the results of tests performed at NETL, demonstrating a capability of replicating many of the observed stability characteristics.
Ph. D.

Incorporation of chemicals into the internal matrix of cement or concrete, with later release occurring upon stimulation, alters the matrix parameters from those at the initial set. Permeability is reduced, for example, and therefore durability enhanced. The advantages of these designs would be the ability to reduce maintenance and repair costs in the initial building configuration and to delay the time of eventual repair. The components and the structure could take greater environmental abuse also. Permeability is significantly reduced by release of a polymer from wax-coated porous fibers upon heating to temperature of polymerization. Freeze/thaw damage is somewhat reduced by the timed release of linseed oil or antifreeze from porous aggregates due to the freezing action itself. These example designs using timed release mostly gave improved durability performance when compared to conventional treatments for durability or environmental distress. Concerns that significant strength reduction would occur due to heating or fiber loading were shown to be unfounded by our test results; indeed, heating and fiber inclusion increased strength. An adequate amount of wetting of the samples could be obtained with 2.75% volume of fibers; however, above a 2.75% volume of fibers, fibers do reduce the strength. Results were analyzed by the method of comparing results in the samples with factors varied to results in samples without variable factors, that is, by comparing to the controls. This research shows that timed internal release of chemicals into cement can be accomplished; it appears feasible and is potentially useful. Long-term tests need to be performed on such factors as chloride ion intrusion/ corrosion tests. Filled fiber, aggregate or prill manufacture, storage, and placement need to be researched and assessed for cost. Design of components using only targeted areas for release in the component and the use of time released fibers in reinforced cement laminates should be evaluated.
Ph. D.

Dans le domaine pharmaceutique, la voie orale demeure la voie d’administration de prédilection, car plus simple et mieux acceptée par les patients. Cependant, ce mode d’administration pose problème pour de nombreux principes actifs (PA) présentant une faible solubilité, une faible perméabilité et/ou une instabilité dans l’environnement gastro-intestinal. Leur micro-encapsulation dans des matrices polymériques peut permettre d’y répondre, notamment si les microparticules générées résistent aux environnements rencontrés lors du tractus gastro-intestinal et jouent alors un rôle protecteur, tant pour le principe actif que pour les muqueuses rencontrées. La recherche de nouveaux excipients, issus des agro-ressources tels que les polymères naturels, est en plein essor. Les protéines végétales, grâce à leurs propriétés fonctionnelles telles qu’une bonne solubilité, une viscosité relativement basse, et des propriétés émulsifiantes et filmogènes, représentent des candidats privilégiés. De plus, la grande diversité de leurs groupements fonctionnels permet d’envisager des modifications chimiques ou enzymatiques variées. L’objectif de ce travail était d’étudier l’intérêt de la protéine de soja en tant que matériau enrobant de principes actifs pharmaceutiques destinés à la voie orale, et plus particulièrement en tant que candidat pour l’élaboration de formes gastro-résistantes. Un isolat protéique de soja (SPI) été utilisé comme matière enrobante et l’atomisation comme procédé. L’ibuprofène, anti-inflammatoire non stéroïdien, a été choisi comme molécule modèle du fait de sa faible solubilité nécessitant une amélioration de sa biodisponibilité, et de ses effets indésirables gastriques nécessitant une mise en forme entérique. Deux modifications chimiques des protéines (l’acylation et la succinylation) ont été étudiées dans le but de modifier la solubilité de la protéine de soja. Ces modifications ont été effectuées dans le respect des principes de la Chimie Verte, notamment en absence de solvant organique. Les microcapsules obtenues par atomisation ont été caractérisées en termes de taux et efficacité d'encapsulation, morphologie et distribution de tailles des particules, état physique du PA encapsulé et capacité de libération en milieu gastrique et intestinal simulé. Les résultats obtenus ont permis de valider l’intérêt des modifications chimiques de la protéine de soja pour moduler les cinétiques de libération d’actif. Les modifications chimiques sont apparues particulièrement adaptées pour l’encapsulation de principes actifs hydrophobes, et ont permis de l’obtention de cinétiques de libération d’ibuprofène ralenties à pH acide (gastrique). La dernière partie de ce travail a permis de valider cette dernière hypothèse par la réalisation de formes gastro-résistantes sur le modèle des comprimés MUPS (multiple unit pellet system). Les résultats de ce travail exploratoire démontrent que les protéines de soja, associées à un procédé de mise en forme multi-particulaire couplé à de la compression directe, peuvent constituer une alternative biosourcée, respectueuse de l’environnement (manipulation en solvant aqueux, temps de séchage et étapes de compression réduits) et sûre à l’enrobage utilisé dans les formes gastro-résistantes traditionnelles
In the pharmaceutical field, the oral route remains the preferred route of administration because it is simpler and better accepted by patients. However, this mode of administration is problematic for many active pharmaceutical ingredients (API) with low solubility, low permeability and/or instability in the gastrointestinal environment. Their microencapsulation in polymeric matrices can make them able to respond to these factors, especially if the microparticles generated resist the environments encountered during the gastrointestinal tract and then play a protective role, both for the API and for the mucous membranes encountered. The search for new excipients, from agroresources such as natural polymers, is booming. Vegetable proteins, thanks to their functional properties such as good solubility, relatively low viscosity, and emulsifying and film-forming properties, are preferred candidates. In addition, the great diversity of their functional groups makes it possible to envisage various chemical or enzymatic modifications. The aim of this work was to study the interest of soy protein as a coating material for API intended for the oral route, and more particularly as a candidate for the development of gastro-resistant forms. A soy protein isolate (SPI) was used as a coating material and the atomization as a process. Ibuprofen, a nonsteroidal anti-inflammatory drug, was chosen as a model molecule because of its low solubility requiring an improvement in its bioavailability, and its gastric side effects requiring an enteric shaping. Two chemical modifications of proteins (acylation and succinylation) have been studied in order to modify the solubility of the soy protein. These modifications were carried out in accordance with the principles of Green Chemistry, especially in the absence of organic solvent. The microcapsules obtained by spray-drying were characterized in terms of rate and encapsulation efficiency, morphology and size distribution of the particles, physical state of the encapsulated API and capacity of release in simulated gastric and intestinal medium. The results obtained validated the interest of the chemical modifications of the soy protein to modulate the release kinetics of API. The chemical modifications appeared particularly suitable for the encapsulation of hydrophobic active ingredients, and allowed to obtain ibuprofen release kinetics decreased to acidic pH (gastric). The last part of this work allowed to validate this last hypothesis by the realization of gastro-resistant forms on the model of MUPS tablets (multiple unit pellet system). The results of this exploratory work demonstrate that soy protein, combined with a multiparticle shaping process coupled with direct compression, can be a biosourced, environmentally friendly alternative (aqueous solvent handling, drying and compression steps reduced) and confident to the coating used in traditional gastroresistant forms

Decision-making models have, m the recent years, been developed to provide systematic and comprehensive tools to analyse, evaluate and manage freight movement. Freight transport models developed thus far have not precisely defined risk agents brought by travelling vehicles, which lead to indistinct risk types. Instead, most of the models developed discussed the risks mainly related to direct impacts by traffic accidents. On the other hand, transport efficiency, which is of more and more concern, has not been sufficiently emphasised in the previous models. This thesis studies the factors in relation to not only safety issues, but efficiency issues. And the risks due to freight movement have been classified into categories in accordance with their distinct natures and typically, affected population groups including human, environment and economic infrastructure. Two new theories, risk agent and risk response factor, have been introduced to the framework to precisely define and evaluate various risk types. Vehicle travelling on a specific route may encounter various situations combined by road characteristics, traffic flow and weather conditions, etc. In order to assist in analysing freight movement in a systematic manner, freight movement behaviours, which pose negative impacts to nearby population, are divided into different modes, which have been interpreted as "risk-producing activities" in the Risk-based Framework for Freight Movement Analysis (RBF-FMA) in order to identify the characteristics of the risk agents. It is important to differentiate the segments with significant changes in the travel risk producing conditions. This study divides travel route into segments and each segment is assessed separately and differentiates among three segment types: travel segment, intersection, and roundabout according to their different contributing factors. The framework developed in this study also considers the availability of emergency response facilities and support system as a major risk-reducing factor. When applied and compared with the risk rating results estimated by the Queensland Transport Department (QTD) using their risk-rating model, the RBF-FMA gave highly comparable results. In the evaluation, both the QTD and RBF-FMA models were applied to assess the risk associated with the release of hazardous mate1ials at 25 segments identified as having high risk by the QTD. The RBF-FMA was also successfully applied to compare two routes between two common points and the results were generally consistent with the concentration of human population, enviromnental population and economic activity and infrastructure along the two routes. The basic data that was needed to conduct the RBF-FMA was easily generated using site visits and from available data basis. While the RBF-FMA presents a logical framework that is based on the risk assessment and management methodology, the process of assigning scores (ranks) and weights to the various factors and sub-factors is basically subjective and reflects the education, values, judgement and understanding of the model by the user. It is recognised that this subjectivity can lead to viability in the results. The contribution of this study is significant in that it translates the basic risk assessment model used in the public health field into a framework suitable for rating the risk associated with freight movement. In addition, the effort presented a basic modelling approach that can be modified or built on by other researchers in this field. The framework formulated in this study is worthy of further research and development as it can be used as a useful system for making decisions related to moving freight along selected routes. Further work could include development of a GIS-based computer program which is able to contain huge amount of risk assessment data associated with freight movement and provide a visual operation of the risk analysis.

Spark ignited engines are still important for conventional as well as for hybrid power trains and are thus objective to optimization. Today a lot of functionalities arise from software solutions, which have to be calibrated. Modern engine technologies provide an extensive variability considering their valve train, fuel injection and load control. Thus, calibration efforts are really high and shall be reduced by introduction of virtual methods. In this work a physical 0D combustion model is set up, which can cope with a new generation of spark ignition engines. Therefore, at first cylinder thermodynamics are modeled and validated in the whole engine map with the help of a real-time capable approach. Afterwards an up to date turbulence model is introduced, which is based on a quasi-dimensional k-epsilon-approach and can cope with turbulence production from large scale shearing. A simplified model for ignition delay is implemented which emphasizes the transfer from laminar to turbulent flame propagation after ignition. The modeling is completed with the calculation of overall heat release rates in a 0D entrainment approach with the help of turbulent flame velocities. After validation of all sub-models, the 0D combustion prediction is used in combination with a 1D gas exchange analysis to virtually calibrate the modern engine torque structure and the ECU function for exhaust gas temperature with extensive simulations
Moderne Ottomotoren spielen heute sowohl in konventionellen als auch hybriden Fahrzeugantrieben eine große Rolle. Aktuelle Konzepte sind hochvariabel bezüglich Ventilsteuerung, Kraftstoffeinspritzung und Laststeuerung und ihre Optimierungspotentiale erwachsen zumeist aus neuen Softwarefunktionen. Deren Applikation ist zeit- und kostenintensiv und soll durch virtuelle Methoden unterstützt werden. In der vorliegenden Arbeit wird ein physikalisches 0D Verbrennungsmodell für Ottomotoren aufgebaut und bis zur praktischen Anwendung geführt. Dafür wurde zuerst die Thermodynamik echtzeitfähig modelliert und im gesamten Motorenkennfeld abgeglichen. Der Aufbau eines neuen Turbulenzmodells auf Basis der quasidimensionalen k-epsilon-Gleichung ermöglicht anschließend, die veränderlichen Einflüsse globaler Ladungsbewegung auf die Turbulenz abzubilden. Für den Brennverzug wurde ein vereinfachtes Modell abgeleitet, welches den Übergang von laminarer zu turbulenter Flammenausbreitung nach der Zündung in den Vordergrund stellt. Der restliche Brennverlauf wird durch die physikalische Ermittlung der turbulenten Brenngeschwindigkeit in einem 0D Entrainment-Ansatz dargestellt. Nach Validierung aller Teilmodelle erfolgt die virtuelle Bedatung der Momentenstruktur und der Abgastemperaturfunktion für das Motorsteuergerät

碩士
嘉南藥理大學
藥學系
102
Controlled release system has a number of advantages, however various excipients and storage conditions might affect release characteristics as well as chemical structure integrity, and thus many affect system quality. The purpose of this study is to investigates stability of mesalamine by using forced-degradation, and then to study effects of core and coating excipients on drug release. Different percentages of povidone K30 and sodium starch glycolate were used in the core tablet. Various percentages of Eudragit S100 and Povidone K30 were coated on the core tablet to produce delayed-release formulations. The chemical stability of the coated tablet under accelerated stability condition was also evaluated. In summary, the forced degradation tests demonstrate that mesalamine is very stable in acid, UV and heat, but not stable in the base and H2O2. The dissolution results show that mesalamine release rates from core tablet can be controlled by binder and disintegrant. Different percentages and thickness of Eudragit S100 and Povidone K30 coating may control the release profile of the delayed-release formulations. By using accelerated stability condition, we can observe limited of mesalamine degradation and is acceptable according to ICH Q3B.

碩士
國立臺北科技大學
化學工程研究所
101
The enteric coating material coated drug controlled release technology is widely used in solid pharmaceutical, and to delay the release of drugs in the stomach so that it is released in the small intestine. Drugs coated with an enteric coating, there are three main factors: (1) Prevent the active substance in the acidic environment of the stomach degradation (2) To avoid contact with drugs and stomach, causing stomach bleeding and ulcers and other phenomena, prevent stomach digestive function (3) Controlling drug release in the intestine, to achieve effective absorption This experiment is to use the Coating pan coated on prescription drugs as the machines that will pre-coated with an enteric coating materials and medicines, first mixed into a coating solution is sprayed on the sugar pills use spray gun surface coated finish is followed by drying with hot air, it will form a film coating of pharmaceutical, during sieving to obtain adequate particle size, surface area. Received in the 8th and the 10th standard sieve material between the controlled release dosage form enteric coating multiple layers drugs, respectively, weighed appropriate quality control different pH values (artificial gastric juice: pH = 1.2, simulated intestinal fluid: pH = 6.8 , distilled water) buffer, for three groups delayed release in vitro dissolution test, and finally the use of UV measurements controlled release dosage form of this drug release pellets situation. The experimental results show that: I. particles coated controlled release formulations (pellets) and Hydroxypropyl cellulose (Hydroxypropyl cellulose; HPC) and ethyl cellulose (Ethyl cellulose; EC) such as film-coated release after coating for pharmaceuticals effects. II. Film-coated coated factors: (1) The composition of the solution film coated (2) coated with a bowl speed, the amount of coating liquid spray (3) coating process III. In the present study found that, for different controlled release dosage form, or mechanism, and there are differences between the principle, but in the end be able to achieve through the deployment of controlled prescription drugs stable release, and to achieve long-term release of drugs effects.

Antibiotic therapy has been proven to be vital for the treatment of life-threatening bacterial infections. Oral antibiotic therapy, however, results in unwanted side effects such as the intestinal flora destruction, allowing for the colonization of foreign bacteria. This phenomenon results in the occurrence of antibioticassociated diarrhea. Probiotic supplementation has been the choice adjunctive prophylaxis for this condition allowing for the bacterial adhesion of intestinal mucosal binding sites. Probiotic bacteria are, however, susceptible to the bactericidal effects of broad-spectrum antibiotics, resulting in many probiotic formulations being prescribed two hours after the ingestion of the antibiotic formulation. This is, however, not always adhered to, with many patients taking the antibiotic and probiotic concomitantly resulting in the destruction of the probiotic bacteria. This study provides for the design, development, characterization and evaluation of an oral delivery system for the concurrent administration of antibiotics and probiotics employing a dual release mechanism or ‘Dual-Biotic System’. The premise behind the development of this system is to allow for the concurrent administration of antibiotics and probiotics where the probiotic bacteria are only released two hours after the antibiotic, in which time the antibiotic would be absorbed into systemic circulation, preventing physical interaction between the systems and thus preventing bacterial destruction. Amoxicillin was chosen as the model antibiotic in this study due to its spectrum of activity and wide utilization in oral antibiotic therapy.

碩士
嘉南藥理科技大學
生物科技研究所
95
The purpose of this study is to prepare and evaluate enteric coated pellets after extrusion/spheronization. The various formulation variables studied, including pellet size, amount of enteric polymer (coating thickness) and soluble polymer/enteric polymer ratio were found to affect drug release kinetics in various dissolution media. Both Didanosine and Doxycycline Hyclate were used as model drugs. Didanosine (DDI) is known to be effective in the treatment of patients with HIV virus by inhibiting HIV replication. DDI is an acid labile drug, therefore it has to be coated with enteric polymer in order to protect the drug in the stomach and to be released in intestine. Doxycycline Hyclate belongs to Tetracyclines antibiotics. DXH is irritant to stomach, thus to release the drug in intestine via enteric coating is necessary to reduce adverse effects. In the process of preparing drug containing pellets, the uncoated pellets are formed using extrusion/spheronization methodology. The granulation solvent mixed with the model drug and water soluble materals, a binder, and a disintegrant, to form a wet mass. The wet mass was extruded/spheronized and then dried to form uncoated pellets. Enteric coating of model drug are available after polymer coating process. Various formulation variables, including pellet size, amount of enteric polymer (coating thickness) and soluble polymer/enteric polymer ratio were found to affect drug release kinetics. On the pellet size, formulations with larger size have slower release rate. Uncoated pellets have faster drug release, where as pellets with thicker polymer coating results in slower drug release. Finally, pellets with higher HPMCP/HPMC ratio of polymer coating results in slower drug release. According to the results, via adjusting appropriate formulation variables, delayed release of model drugs is achievable in order to avoid drug degradation and drug irritation in stomach.

The influence of plasticization and other formulation factors on the properties of hot-melt extruded dosage forms for the controlled release of water-soluble active compounds was investigated. Citric acid monohydrate was demonstrated to function as a solid-state plasticizer in hot-melt extruded Eudragit® RS PO tablets and in cast films when concentrations below the compatibility limit were employed. Melting of the organic acid and solubilization in the polymer during extrusion were necessary to observe the plasticizing effect. The release rate of diltiazem hydrochloride, used as a high-melting, water-soluble model drug, from melt extruded Eudragit® RS PO matrix tablets increased and became independent of the original drug particle size in the presence of citric acid monohydrate. Thermal analysis of physical mixtures demonstrated that citric acid promoted drug melting during extrusion by interaction and melting point depression. Diltiazem hydrochloride remained amorphous in the final dosage form, and leaching of citric acid monohydrate enhanced drug diffusion by increasing the matrix porosity. Delayed-release matrix pellets with particle sizes below one mm were prepared by hot-melt extrusion, and the influence of the matrix forming polymer and the type and level of plasticizer on the processibility and release properties was investigated. Pellets complied with the USP requirement for delayed release articles to release less than 10% drug at pH 1.2 after 2 hours when plasticized Eudragit® S100 was used as the release-controlling material. High levels of efficient plasticizers had to be employed to decrease the polymeric melt viscosity, increase the process yield and enable extrusion at moderate temperatures to avoid instabilities during processing and storage. The aqueous solubility of the plasticizer further impacted the drug release rate in acid. A novel application of hot-melt extrusion for the preparation of monolithic matrices comprising enteric coated particles was studied. The influence of the mechanical strength of the multiparticulates, pellet loading and nature of the hydrophilic carrier material on the preservation of the delayed-release properties after extrusion was investigated. Soft particles coated with brittle films remained intact when low-melting carriers that did not solubilize the enteric film during extrusion were used, and the dissolution profile was stable over one year.
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Background and Aim: The common brushtail possum (Trichosurus velpecula) causes more damage to the environment than any other vertebrate species in New Zealand. The use of poison remains the main method for possum population control. Diphacinone is an anticoagulant that produces toxic effects by inhibiting the production of vitamin K–dependent coagulation factors which lead to profuse haemorrhage and eventually, death. The objective of this thesis was to investigate the potential of diphacinone as a toxin for the control of possum population in New Zealand. Methods: The preformulation of diphacinone included the development and validation of an analytical method, spectral identification, investigation of melting behaviour, solubility, and the determination of ionisation constant. The permeability of diphacinone across the ileal tissue of possum was assessed using a modified Ussing chamber model. Diphacinone granules were developed to prolong drug release and retention by in vitro dissolution and tensile testing. A factorial study was employed to optimise the granulation process by identifying significant process variables that influenced the yield percentage, size distribution and water uptake of granules.

Zhang, Xinran.
Thesis submitted in: December 2007.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2008.
Includes bibliographical references (leaves 80-87).
Abstracts in English and Chinese.
TITLE PAGE --- p.i
ABSTRACT --- p.ii
中文摘要 --- p.v
ACKNOWLEDGEMENTS --- p.vii
TABLE OF CONTENTS --- p.viii
LIST OF FIGURES --- p.xi
LIST OF TABLES --- p.xiv
ABBREVIATIONS --- p.xv
Chapter CHAPTER 1. --- Introduction
Chapter 1.1. --- Rationale of the Study --- p.1
Chapter 1.2. --- Current technologies for formulating long-acting parenteral protein deliver system --- p.3
Chapter 1.2.1. --- Chemical Modification --- p.3
Chapter 1.2.2. --- Sustained-release formulation --- p.4
Chapter 1.2.2.1. --- Phase separation method --- p.4
Chapter 1.2.2.2. --- Solvent evaporation/extraction method --- p.5
Chapter 1.2.2.3. --- Spray drying method --- p.6
Chapter 1.2.2.4. --- Causes for protein instability --- p.6
Chapter 1.2.2.4.1. --- Water/organic solvent interface --- p.6
Chapter 1.2.2.4.2. --- Lyophilization --- p.8
Chapter 1.2.2.4.3. --- Polymer --- p.11
Chapter 1.2.2.4.4. --- Stabilizing additive --- p.13
Chapter 1.3. --- Aqueous-aqueous emulsion technology --- p.17
Chapter 1.3.1. --- Background --- p.17
Chapter 1.3.2. --- Basic Principle --- p.17
Chapter 1.3.3. --- Phase diagram --- p.18
Chapter 1.3.4. --- Formation of aqueous-aqueous emulsion --- p.19
Chapter 1.3.4.1. --- Introduction of a water-soluble charged polymer as stabilizer --- p.19
Chapter 1.3.4.2. --- Freezing-induced phase separation --- p.20
Chapter 1.3.5. --- General Protocol --- p.21
Chapter 1.3.5.1. --- Introduction of a water-soluble charged polymeric stabilizer --- p.22
Chapter 1.3.5.2. --- Freezing-induced phase separation --- p.22
Chapter 1.3.6. --- Merits and limitations of the aqueous-aqueous emulsion technology --- p.23
Chapter 1.3.7. --- Protein selection for the sustained release formulation --- p.25
Chapter 1.4. --- Aims and scope of study --- p.26
Chapter "CHAPTER 2," --- Materials and Methods
Chapter 2.1. --- Materials --- p.28
Chapter 2.1.1. --- Proteins --- p.28
Chapter 2.1.2. --- Polymers --- p.28
Chapter 2.1.3. --- Media for TF-1 Cell Culture --- p.28
Chapter 2.1.4. --- Chemicals and Solvents for Cell Proliferation Assay --- p.29
Chapter 2.1.5. --- Other Chemicals and Solvents --- p.29
Chapter 2.1.6. --- Materials for Cell Culture --- p.29
Chapter 2.1.7. --- Materials for Reagent Kits --- p.30
Chapter 2.2. --- Methods --- p.30
Chapter 2.2.1. --- Determination of the Partition Coefficients of Proteins Between PEG and Dextran --- p.30
Chapter 2.2.2. --- Preparation of Glassy Particles --- p.31
Chapter 2.2.2.1. --- Standard Stable Aqueous-aqueous Emulsion Method --- p.31
Chapter 2.2.2.2. --- Freezing-induced Phase Separation --- p.32
Chapter 2.2.3. --- Preparation of Protein-loaded and Blank Microspheres Using S-o-w Solvent Extraction Technique --- p.32
Chapter 2.2.4. --- Optical Microscopy and Scanning Electron Microscopy --- p.33
Chapter 2.2.5. --- Determination of Protein Loading --- p.34
Chapter 2.2.5.1. --- Within Dextran Particles --- p.34
Chapter 2.2.5.2. --- Within PLGA microspheres --- p.34
Chapter 2.2.6. --- Evaluation of Protein Structural Integrity and Bioactivity in Dextran Particles and PGLA Microspheres --- p.35
Chapter 2.2.7. --- In vitro Release Study --- p.36
Chapter 2.2.8. --- RhIFN Stability Determination under Simulated In Vitro Release Conditions --- p.37
Chapter 2.2.8.1. --- In the Absence of PLGA --- p.37
Chapter 2.2.8.2. --- In the Presence of PLGA --- p.37
Chapter 2.2.9. --- MicroBCÁёØ Protein Assay --- p.38
Chapter 2.2.10. --- Size Exclusion Chromatography (SEC) - High Performance Liquid Chromatography (HPLC) --- p.38
Chapter 2.2.11. --- ELISA --- p.39
Chapter 2.2.12. --- Bioactivity Assay --- p.40
Chapter 2.2.12.1. --- RhIFN --- p.40
Chapter 2.2.12.2. --- RhGM-CSF --- p.41
Chapter CHAPTER 3. --- Results and Discussions
Chapter 3.1. --- Sustained-release RhIFN Formulation --- p.45
Chapter 3.1.1. --- Partition Coefficient of RhIFN --- p.45
Chapter 3.1.2. --- Formulation Based on the Standard Aqueous-aqueous Emulsion (SA-AE) Method With Sodium Alginate as Stabilizer --- p.45
Chapter 3.1.2.1. --- Surface Morphology --- p.45
Chapter 3.1.2.2. --- Formulation Characterization --- p.46
Chapter 3.1.2.3. --- In Vitro Release of RhIFN from PLGA Microsheres --- p.54
Chapter 3.1.3. --- Formulation Based on the Freezing-induced Phase Separation (FIPS) Technique without Sodium Alginate --- p.56
Chapter 3.1.3.1. --- Formulation Characterization --- p.56
Chapter 3.1.3.2. --- In Vitro Release of RhIFN from PGLA Microsphees --- p.59
Chapter 3.2. --- RhIFN Stability Assessment under Simulated In Vitro Release Conditions --- p.63
Chapter 3.2.1. --- In the Absence of PLGA --- p.63
Chapter 3.2.2. --- In the Presence of PLGA --- p.65
Chapter 3.3. --- Sustained-release RhGM-CSF Formulation --- p.68
Chapter 3.3.1. --- Partition Coefficient Determination of RhGM-CSF Between PEG and Dextran --- p.68
Chapter 3.3.2. --- Formulation Based on Freezing-induced Phase Separation --- p.68
Chapter 3.3.2.1. --- Validation of MTT Assay Conditions --- p.69
Chapter 3.3.2.2. --- Formulation Characterization --- p.71
Chapter 3.3.2.3. --- In Vitro Release of RhGM-CSF from PLGA Microspheres --- p.75
Chapter CHAPTER 4. --- Conclusion and Future Studies
Chapter 4.1. --- Conclusion --- p.78
Chapter 4.2. --- Future Studies --- p.79
References --- p.80

The auditory brainstem is comprised of a number of synapses specialized for the transmission of high-fidelity synaptic signals. Within the first three postnatal weeks, these pathways acquire the ability to process high-frequency signals without compromising timing information. However, little is known regarding developmental adaptations which confer this ability. Situated in the sound localization pathway, the calyx of Held-medial nucleus of the trapezoid body synapse provides an ideal model for investigating such adaptations as both the pre- and postsynaptic neurons are accessible to electrophysiological experimentation. Using this synapse, we have shown herein that the spatial coupling between voltage-gated calcium channels (VGCCs) and synaptic vesicles (SVs) tightens during development. Immature synapses use a loosely-coupled arrangement of many N- and P/Q-type VGCCs (“microdomain” modality) while mature synapses use a tightly-coupled arrangement of fewer P/Q-type VGCCs, to release SVs (“nanodomain” modality). As a consequence of this tightening, synaptic delay (SD) shortens. By fluorescence- and electron microscopy of SVs near active zones, we further identified the filamentous protein septin 5 as a molecular substrate, differentiating the two release modalities, which may act as a spatial barrier separating VGCCs and SVs in immature synapses. Finally, we have demonstrated that changes in release modality affect the nature of short-term plasticity observed at this synapse. Using trains of action potentials as presynaptic voltage-commands, we showed that, downstream of calcium influx, the microdomain modality promotes short-term facilitation in excitatory postsynaptic currents (IEPSC), and calcium-dependent decreases in SD, with these being absent in synapses employing the nanodomain modality. In contrast, we found that as a result of depletion of SVs, short-term depression of IEPSC dominates in synapses using the nanodomain modality, and correlates with calcium-dependent increases in SD. These findings imply that the type of release modality has a significant impact on the strength and timing of synaptic responses. The microdomain modality imparts greater dynamic range in timing and strength, but does so at the cost of efficiency and fidelity, while the nanodomain modality is a key accomplishment consolidating the high-fidelity abilities of this synapse.

Yes
A new type of self-assembled polyelectrolyte complex nanocarrier composed of chondroitin (CHON) and protamine (PROT) was designed and the ability of the carriers to bind salmon calcitonin (sCT) was examined. The response of sCT-loaded CHON/PROT NPs to a change in the properties of the liquid medium, e.g. its pH, composition or ionic strength was studied and in vitro peptide release was assessed. The biocompatibility of the NPs was evaluated in Caco-2 cells. CHON/PROT NPs were successfully obtained with properties that were dependent on the concentration of the polyelectrolytes and their mixing ratio. X-ray diffraction determined the amorphous nature of the negatively charged NPs, while those with the positive surface potential were semi-crystalline. sCT was efficiently associated with the nanocarriers (98-100%) and a notably high drug loading (13-38%) was achieved. The particles had negative zeta potential values and were homogenously dispersed with sizes between 60 and 250 nm. CHON/PROT NPs released less than 10% of the total loaded peptide in the first hour of the in vitro release studies. The enthalpy of the decomposition exotherm correlated with the amount of sCT remaining in NPs after the release experiments. The composition of medium and its ionic strength was found to have a considerable influence on the release of sCT from CHON/PROT NPs. Complexation to CHON markedly reduced the toxic effects exerted by PROT and the NPs were compatible and well tolerated by Caco-2 cells.