Dissertations / Theses on the topic 'Release'

Thesis (Ph. D.) -- University of Maryland, College Park, 2004.
Thesis research directed by: Chemical Engineering. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.

This study has investigated the drug release mechanisms from hydroxypropyl methylcellulose (HPMC) hydrophilic matrices. A hypothesis was developed from interpretation of a previous study that drug surface activity has an influence on drug liberation. The validity of the hypothesis was tested by studying the interactions between HPMC and the two non-steroidal anti-inflammatory drugs diclofenac Na and meclofenamate Na, using tensiometry, rheology, NMR, neutron scattering and turbimetry. Meclofenamate Na was found to interact with HPMC, resulting in detectable changes in drug diffusion coefficients and polymer structure in solution. There were increases in HPMC solution solubility and changes in viscoelasticity, which suggested drug solubilisation of the methoxyl-rich regions of the polymer chains. Diclofenac Na did not show evidence of an interaction and exhibited changes consistent with a 'salting out' of the polymer. A confocal microscopy technique was used to image the drug effects on early gel layer development. The presence of drugs affected gel layer development, depending on the level of drug in the matrix and the concentration of sodium chloride in the hydration medium. Diclofenac Na matrices became increasingly susceptible to disintegration, while meclofenamate Na matrices exhibited resistance to the effects of sodium chloride. The influence of incorporated diluents on the gel layer was also investigated and it was found that lactose had a disruptive effect, whereas microcrystalline cellulose was relatively benign. When co-formulating drugs and diluents in the matrix, lactose acted to antagonise the effect of meclofenamate, but acted synergistically with diclofenac to reduce gel layer integrity and accelerate matrix disintegration. In contrast, MCC was found to have a relatively neutral effect on drug-mediated effects. HPMC particle swelling and coalescence are critical processes in gel layer formation extending drug release. Drug surface activity and capability of interacting with HPMC appears to influence particle swelling processes, affecting gel layer formation and provides a mechanistic explanation for the differing release profiles of diclofenac and meclofenamate Na.

Avalanche occurrence is closely related to the local meteorological conditions which may be quite variable in mountain topography. To investigate these conditions, and to provide information for avalanche forecasting, we designed and built a weather station which is currently relaying information to a base station from a remote site. Most field tests of snow do not adequately describe the engineering properties. In this study, we wanted to design some tests which would measure such properties and also provide an estimate of snow slope stability. Our tests of shear and tensile strength of snow were designed to simulate as closely as possible conditions expected in a naturally occurring snow slab, and were made in-situ using large samples. We describe several sets of measurements made across crownwalls after avalanche release. Such measurements typically showed considerable spatial variability and in 4 cases out of 5, a probabilistic approach combined with a simple force balance provided a satisfactory indication of the likelihood of failure. From the results or this analysis, we proposed a new field test to estimate stability. This test requires only a snow saw and is simple and quick to complete. It is well known that the strength of materials depends on strain-rate, and we made some measurements using a strain gauge in conjunction with the simple field tests. Although the rates applicable during snow avalanche release are uncertain, investigations or such properties provides an insight into release mechanisms. A device to measure air permeability of snow in the field was designed and built. Results from measurements showed that air permeability gave a good measure of snow structure which is related to strength. We think most of the variability of snow strength originates from air-flow patterns above the slope during storms, and further studies concerning these patterns could define the location of weak zones within a snow pack. Such information would enhance understanding of release mechanisms, and also improve avalanche forecasts.

Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2003.
Includes bibliographical references (leaf 34).
Microchips for constant release are not a new concept, but a controlled release chip, which does pulsatile release at variable time intervals, is clearly more efficient and useful. The process was completely understood about the theory of operation, the manufacturing procedure and the robustness of the controlled release microchip. The complete application analysis has been done along with the intellectual property study. The study involved finding out the industry opinion of the device and the usefulness of the device and all the people who might have intellectual property rights in the field. As a result numerous applications of the device have been found out along with the important parameters the device should be concentrating on have been suggested.
by Lalita Varma V. Pakalapati.
M.Eng.

Amphiphilic polymers have long been known to display associative effects which can be exploited in controlled release applications. In particular, controlled drug delivery can benefit from the biocompatible nature of many polymers, as well as evidence of membrane affinity. This thesis describes the study of a series of amphiphilic polymers with potential for use in pharmaceutical applications. The work has ranged from development of new polymer structures with physical characteristics which may aid controlled release, through studies of polymer-drug association and disassociation in solution, to development of controlled release formulations incorporating the polymers. Novel polymers combining the controlled release potential of Pluronic triblock copolymers with that of cyclodextrins have been synthesised, via "Click Chemistry". The specificity and strong driving force behind this mechanism ensure that the molecules react covalently, to leave the cyclodextrin cavity free for complexation and controlled release of guest molecules. Commercial (unmodified) Pluronics have also been studied with drug molecules in solution, using small-angle neutron scattering and pulsed-field gradient NMR. Ibuprofen has been found to act as a cosurfactant for the Pluronic, causing an increase in aggregation but a decrease in the critical micelle concentration and temperature. Release of ibuprofen from the micelles may be triggered by an increase in solution pH, which influences the dynamic equilibrium of ibuprofen between the solution and micellar phases. Finally, new graft copolymers of polyisoprene and poly( ethylene oxide) have been found to display interesting behaviour in aqueous solution. Despite showing limited aqueous solubility, the polymers can be solubilised either by addition of other surfactant molecules, or by pre-dissolution in methanol, which is believed to enable the hydrophilic graft segments to orient outwards. The graft copolymers are capable of stabilising hydrophobic drug molecules in aqueous solution, and have also been successfully incorporated into controlled release formulations for drug delivery.

A thesis submitted to the College of Dental Medicine of Nova Southeastern University of the degree of Master of Science in Dentistry. Objectives: To determine the amount of initial fluoride release from four orthodontic bonding systems over a period of four weeks, and then to subject these materials to an external source of fluoride for recharge in order to measure the amount of fluoride re-release over another four-week interval. Additionally the surface morphology of these materials was analyzed under the scanning electron microscope in order to identify microscopic changes in the materials that may have occurred during the experiment. Methods: Four orthodontic adhesives: Fuji Ortho LC (GC America, Alsip, IL), Transbond XT (3M Unitek, Monrovia, CA), Illuminate Light Cure (Ortho Organizers, Carlsbad, CA), and Opal Seal with Opal Bond MV (Ultradent, South Jordan, UT), n=120 (30/material) were tested for fluoride release at 1 hour, 24 hours, 3 days, 1 week, 2 weeks, 3 weeks and 4 weeks. Samples (10/subgroup/material) were then recharged with an external source of fluoride (toothpaste, foam, or varnish), and retested for fluoride re-release at 1 hour, 24 hours, 3 days, 1 week, 2 weeks, 3 weeks and 4 weeks. The scanning electron microscope was utilized in order to assess each material's surface morphology before testing and after completion of the experiment (n=16). Descriptive statistics, means and standard deviations were calculated for all four materials and their subgroups at each time interval. A mixed model two-way ANOVA was run, using a level of significance of 0.05. Bonferroni multiple comparison tests were conducted using if groups were found to be statistically significantly different. To determine significant differences between fluoride release and re-release for each recharge subgroup within each material group, paired t-tests were performed for the time intervals of 24 hours, 2 weeks, and 4 weeks. For the paired t-tests, the level of significance used was 0.02 to allow for Bonferroni correction. Results: During the initial 24 hours the fluoride measurements (in mg/L or ppm) were as follows: Fuji 9.78±0.65, Illuminate 7.83±1.49, Opal 0.05±0.02, and Transbond 0.01±0.0. At the initial four weeks time point, the readings were as follows: Fuji 6.68±0.79, Illuminate 3.82±1.84, Opal 0.06±0.01, and Transbond 0.01±0.01. The greatest fluoride release came from the varnish subgroups from each of the materials at 2 weeks post re-charge: Fuji 9.16±1.53, Illuminate 7.5±3.1 (tied with foam subgroup 7.5±4.4), Opal 5.3±2.45, and Transbond 3.75±1.67. The greatest fluoride measurement for each material at the final week post-recharge was: Fuji varnish subgroup 8.3±3.58, Illuminate foam subgroup 6.5±3.5, Opal varnish subgroup 2.50±1.1, and Transbond varnish subgroup 1.72±1.82. SEM results showed an observable difference between the materials pre-experiment and post-experiment at a magnification of 50X and 500X. The Fuji foam and paste subgroups displayed surface crackling patterns at both magnifications when compared to the control and varnish samples. The Illuminate control, foam, and paste specimens all had a roughened grainy appearance, while the varnish specimen seemed to be smoothed over by the varnish material. The Transbond samples appeared to have observable differences in surface morphology at 50X, but not at 500X. The Opal paste and foam specimens appeared to have a smoother surface than both the control and the varnish samples. Conclusions: There were significant differences in release and re-release of fluoride among all four adhesives at different time intervals over a period of eight weeks. Significant increase in fluoride re-release was seen for all three of the recharge subgroups for both Opal and Transbond at each time interval. A significant increase in fluoride re-release for the Illuminate group was mainly observed at the end of second and fourth week. Though no significant increase in fluoride re-release was observed, Fuji released highest amount of fluoride during release and re-release, at all different time intervals. Fluoride varnish was the superior recharge material, as it provided the greatest fluoride measurements, followed by foam and toothpaste. There were observable changes in the surface morphology of the materials pre-experiment and post-experiment at a magnification of 50X and 500X, which may have an affect on the fluoride releasing capabilities of the materials.

L’objectiu d’aquest projecte de doctorat és millorar el rendiment dels dispositius Air Care que desenvolupen una membrana que pot alliberar les matèries primeres de perfum carregades a l’interior de l’embassament sense ser extremadament afectades per les fluctuacions de temperatura del medi extern, sent així menys significatives. sensible a la temperatura que la membrana actual usada en els productes actuals. Per fer-ho, la membrana principal es recobrirà amb un polímer modificat amb nous fragments d’azobenzen. Aquest sistema es pot desencadenar per la llum perquè actuï com una porta intel·ligent per a la difusió del perfum, millorant tant la selectivitat com alliberant el control de les matèries primeres de perfum a l’entorn de la llar / cotxe. A més, mitjançant un disseny adequat de la unitat funcionalitzadora, la temperatura podria actuar com a estímul extern addicional, capaç de desencadenar convenientment (és a dir, reduir) la permeabilitat de la membrana mitjançant una isomerització tèrmica posterior.
El objetivo de este proyecto de doctorado es mejorar el rendimiento de los dispositivos Air Care que desarrollan una membrana que puede liberar las materias primas de perfume cargadas dentro del depósito sin verse extremadamente afectadas por las fluctuaciones de temperatura del ambiente externo, por lo tanto, ser significativamente menos sensible a la temperatura que la membrana actual utilizada en los productos actuales. Para hacer esto, la membrana principal se recubrirá con un polímero modificado con nuevos restos de azobenceno. La luz podría activar este sistema para que actúe como una puerta inteligente para la difusión del perfume, mejorando tanto la selectividad como liberando el control de las materias primas del perfume en el entorno del hogar / automóvil. Además, mediante un diseño adecuado de la unidad funcionalizadora, la temperatura podría actuar como un estímulo externo adicional, capaz de disparar convenientemente (es decir, reducir) la permeabilidad de la membrana a través de la isomerización térmica.
The objective of this PhD project is to improve the performance of Air Care devices developing a membrane that can release the perfume raw materials charged inside the reservoir without being extremely affected by temperature fluctuations of the external environment, thus, being significantly less temperature sensitive than the current membrane used in nowadays products. In order to do this the main membrane will be coated with a polymer modified with novel azobenzene moieties. This system could be triggered by light to act as an intelligent gate for the perfume diffusion, improving both selectivity and releasing control of the perfume raw materials in the home/car environment. In addition, by a proper design of the functionalizing unit, temperature could act as an additional external stimulus, able to conveniently trigger (i.e. reduce) membrane permeability through thermal back-isomerization.

Control release from biopolymer is an important issue for flavour perception following to reduce flavour content such as salt in food formulation without any tangible change in taste. The experiments presented release behaviour from low acyl gellan gum gel. Attempts were focused to find a link between mechanical properties and microstructure of the gel. After conducting the compression tests, a number of parameters were investigated and the consist of the effect of the gellan concentration, salt concentration and cyclic compression on the mechanical properties of the gel. According to the results, mechanical properties of the gellan gels were remarkably affected by the gellan concentration, salt concentration and cyclic compression. It was shown that the gellan concentration, salt concentration and cyclic compression play a main role on the microstructure of the gel. The release experiments were carried out using uniaxial and cyclic compression to investigate the salt and riboflavin release from the gellan gel to identify the parameters which play a role on release from the gellan gel. Release experiments have shown that release profile is affected by the gellan concentration, salt concentration and number of cyclic compression. Results demonstrated that release profile can be affected by molecular weight of the releasable material.

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1999.
"September 1999."
Includes bibliographical references.
It is well known that the method by which a drug is delivered can have a significant effect on the drug's therapeutic efficacy. There exist numerous cases where constant release is not the optimal method of drug delivery; instead, delivery of pulses of drug at variable time intervals is the preferred method. This method is commonly referred to as pulsatile delivery, and it is preferred in some cases because it closely mimics the way in which the human body naturally produces the compounds. The objectives of this thesis were to design, fabricate, and characterize a microchip capable of achieving both pulsatile and continuous release of multiple chemical substances on demand. Each prototype microchip consisted of an array of reservoirs etched into and extending through a silicon wafer. Each reservoir was covered on one end by a thin conductive membrane that served as the anode in an electrochemical reaction. The reservoir was filled with chemicals through the other side of the reservoir and was then sealed. The proposed release mechanism had no moving parts and was based on the electrochemical dissolution of a thin anode membrane covering each reservoir. Each reservoir was independently addressable, and the electric potential was applied to an anode membrane using wires and a potentiostat. Future integration of microelectronic components may allow reservoirs to be opened on demand by a preprogrammed microprocessor, remote control, or by biosensors and biofeedback controllers. Potential advantages of the microchip for the release of drugs and other chemicals may include its small size, low power consumption, and the absence of moving parts. Such microchips may find application in a wide array of fields such as drug delivery, medical diagnostics, chemical detection. industrial process monitoring and control, and micro-scale chemical synthesis. A process was developed for producing prototype microchips using microfabrication methods such as ultraviolet photolithography, chemical vapor deposition (CYD), reactive ion etching (RTE), and electron beam evaporation. An important component of this process was a procedure for making thin ( I 000-3000 [angstroms]), unsupported, metal membrane anodes on silicon. In addition, the fabrication process was designed so that the chemicals to be released would !lever be exposed to solvents, acids, bases, or high temperatures. This was accomplished by completing all device fabrication steps before reservoir filling. This important process feature would be especially useful when dealing with easily denatured molecules such as proteins or DNA. Gold was selected as the model membrane and electrode material for the prototype controlled release microchips primarily due to its unique electrochemical properties. It is easily deposited and patterned, has a low reactivity with other substances, and resists spontaneous corrosion in most aqueous solutions over the entire pH range. However, the presence of a small amount of chloride ion in solution creates an electric potential/pH region that thermodynamically favors the dissolution of gold as water soluble gold chloride complexes. Experiments showed that gold thin films are rapidly corroded in saline solution and that corrosion occurs preferentially in the grain boundaries. Release studies were conducted to demonstrate that single and multiple substances could be released from microchip devices on demand. Sodium fluorescein (a fluorescent dye) and radioactive calcium (in the form, 45CaCI) were chosen as model substances for release due to their simplicity of detection in solution. Prototype devices were filled with one or both substances, sealed, and submerged in either phosphate buffered saline or 0.145 M NaCl solution. A potential of+ 1.04 volts relative to a saturated calomel reference electrode (SCE) was applied between a gold membrane anode covering a filled reservoir and a cathode. Electrochemical dissolution of the gold membrane anode typically occurred within 10-20 seconds of application of the potential. Once the reservoir was opened, the compound in the reservoir was able to diffuse into the surrounding solution and was detected by fluorescence spectroscopy or scintillation counting. This process was repeated to obtain multiple releases from a single device. Disintegration refers to the "falling apart" of a gold membrane over a reservoir resulting from gold corrosion and possibly. applied physical stresses. The visualization of the membrane disintegration process was achieved by videotaping the corrosion of gold membranes through a microscope. The observations from these in situ membrane disintegration experiments were then combined with gold corrosion concepts and data to develop a qualitative mechanism for the disintegration of thin. gold membranes covering chemical reservoirs. Future work should focus on materials science issues, microelectronics fabrication and packaging, and in vivo studies.
by John Thomas Santini, Jr.
Ph.D.

Possessing elements of both dark comedy and dramatic suspense, The Release is the story of Sean Coleman, a young, idealistic documentary filmmaker, who, in fighting for his film's release, discovers that his beliefs may not be as strong as his desire to get what he wants. This paper will examine the total production process that went into the development, creation and finalization of this film.

Inhalation has become an increasingly viable alternate route to oral dosing, with the advantage of treating local disease with minimal systemic side effects (Hickey, 1992). However, increasingly complicated medication regimens associated with the necessity of the repeated dosing of multiple agents used in treating pulmonary disease has been shown to compromise both disease management and patient convenience. In this study the viability of spray drying to introduce controlled release vectors into dry powders for inhalation was investigated. The first experimental section highlights the use of leucine in producing highly respirable spray dried powders, with in vitro respirable fractions (Fine particle fraction, FPF: F < 5µm) exceeding 80% of the total dose. The second experimental chapter introduces the biocompatible polymer chitosan (mw 190 – 310 kDa) to formulations containing leucine with findings of increased FPF with increasing leucine concentration (up to 82%) and the prolonged release of the active markers terbulataline sulfate (up to 2 hours) and beclometasone dipropionate (BDP: up to 12 hours) with increasing chitosan molecular weight. Next, the thesis details the use of a double emulsion format in delivering the active markers salbutamol sulfate and BDP at differing rates; using the polymers poly-lactide co-glycolide (PLGA 50:50 and PLGA 75:25) and/or chitosan incorporating leucine as an aerosolisation enhancer the duration of in vitro release of both agents reaching 19 days with FPF exceeding 60%. The final experimental chapter involves dual aqueous and organic closed loop spray drying to create controlled release dry powders for inhalation with in vitro sustained release exceeding 28 days and FPF surpassing 55% of total loaded dose. In conclusion, potentially highly respirable sustained release dry powders for inhalation have been produced by this research using the polymers chitosan and/or PLGA as drug release modifiers and leucine as an aerosolisation enhancer.

Solutes are often most efficiently deployed in discrete pulses, for example in the delivery of herbicides or drugs. Manual application of each pulse can be labor-intensive, automated application of each pulse can be capital intensive, and both are often costly and impractical. Barrier-Mediated Pulsatile Release (BMPR) systems offer a materials-based alternative for automated pulsatile drug delivery, without pumps, power supplies, or complex circuitry. While earlier materials-based approaches such as delayed-release microcapsules are limited to two or three pulses due to the independent nature of each pulse’s timing control, BMPR systems link the timing of each pulse to the previous pulse. Each dose of drug is sequestered in its own stimuli-sensitive depot, releasing only upon contact with the stimulant. These depots are stacked with sacrificial barriers in between, each of which block the stimulant for a predetermined time. For instance, layers of soluble drug may be separated by degradable polymer layers. Water, as the stimulant, will erode the polymer layer over a fixed period of time, followed by quick dissolution and release of the underlying drug and the start of degradation for the next polymer layer. This example, however, is quickly limited by irregular polymer erosion, a single stimulant (water), and difficulty in scaling delay times. The research work presented in this thesis reports the development of a generalized BMPR system which overcomes those limitations. Model drugs (methylene blue and methyl orange) were immobilized in a pH-sensitive polymer [poly(methyl methacrylate-co-dimethylaminoethyl methacrylate)] which released only at low pH. Zinc oxide (ZnO) nanoparticles immobilized in a pH-insensitive matrix [poly(vinyl alcohol)] served as the barrier layer. The time required for acid to penetrate the barrier layer scaled with the ZnO concentration and with the square of the polymer thickness, allowing wide scaling of the delay time with only minor changes to the barrier layer. Harnessing the swelling pressure of the acid-sensitive hydrogel, each barrier/depot bilayer can delaminate upon solute release, directly exposing the next bilayer to the stimulant source. This system has demonstrated tuned release using a citric acid stimulant to produce up to ten pulses of model drug (methylene blue) over various preset timescales. This system has also demonstrated the alternate release of multiple solutes (methylene blue and methyl orange) at regular time intervals up to five pulses from a single BMPR device. For non-delaminating BMPR systems, spent bilayers impede stimulant diffusion to the inner layers and solute diffusion from the inner layers, increasing the delay time and the pulse width. To predict these changes, a computational model was constructed in FORTRAN. This model was extensively explored over a wide range of parameter space to understand the release behavior of various kinds of non-delaminating BMPR systems. The computer model also validates the performances of experimental delaminating BMPR system. This model can be used to guide the physical modeling of BMPR systems. The model also allows to incorporate variety of stimulants other than just acid. BMPR technology introduces efforts to further generalize the delivery strategy by incorporating glucose as a stimulant.

Controlled release formulations offer many advantages over conventional dosage forms. These include reduced plasma fluctuations and improved patient comp1i:nce. Complex controlled release formulations such as those with enteric release properties, often require additional steps in the production phase. The costs and economic impact associated with these complex controlled release dosage formulations often outweigh the immediate benefits. Thus the development of an economic method to produce controlled release particles is of great importance especially in third world countries. In controlled release formulations, the drug is generally dispersed throughout a polymer matrix. The rate of drug release is often determined by the viscosity or complexity of the polymer matrix through which the drug needs to diffuse in order to be released. With enteric release the polymer coating, insoluble in an acidic environment is often applied in the final phase of production. Chitosan is a versatile polymer of natural origin with many favourable characteristics. These include its safety, biocompatibility, and biodegradability. Simple methods can be applied and modified to produce controlled release particles form chitosan. The effect of modern controlled release polymers such as Aqoat AS-HF, Eudragit SlOO and Kollidon SR was investigated. Chitosan beads and chitosan-polymer beads, as well as chitosan granules and chitosan-polymer granules, were prepared and investigated as possible controlled release formulations. Ketoprofen was chosen as the model drug. Chitosan beads and chitosan-polymer beads were prepared by inotropic gelation in tripolyphosphate. Chitosan granules and chitosan-polymer matrix granules were prepared by binding chitosan with an acetic acid solution as a granulating system. The beads and granules appeared differed in appearance as well as in the results obtained from various experiments. Granules prepared in the study did not appear to be effective with regards to enteric and controlled release. Beads prepared form Kollidon SR appeared to be effective with regards to enteric and controlled release, with Kollidon 1% and 5% w/v chitosan beads achieving good drug loading of up to 73.13% and releasing less than 15 % of the total drug content in 0.1 M HCI after 60 minutes. Drug release continued steadily for up to 360 minutes in pH 7.2. It was concluded that Kollidon SR loaded chitosan beads nay be a viable controlled release dosage form with enteric release properties, and that future experiments, possibly with lower polymer concentrations, are worthwhile
Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2006.

Le développement de nouvelles formes galéniques nécessite la mise au point de protocoles avec variation d’un ensemble de paramètres jouant sur les caractéristiques du dispositif. Au niveau industriel, cela représente une perte importante de temps et d’argent. Avec le développement d’outils permettant la caractérisation des systèmes et à fortiori des mécanismes impliqués dans la libération du principe actif, l’application des modèles mathématiques se voit être de plus en plus grande permettant de prédire la sortie du principe actif hors de son système. L’un des objectifs de ce travail a été de développer un modèle mathématique mécanique réaliste permettant de quantifier la libération de vitamines à partir de matrice lipidique. Deux techniques différentes de formulation : la compression directe et une suite d’extrusion en phase chauffante/ broyage/ compression directe ont permis la préparation de comprimés à base de Compritol 888 (glyceryl dibehenate NF). L’acide nicotinique a été utilisé comme principe actif modèle hautement soluble dans le milieu environnant. Des études de dissolution ont montrée une libération plus accrue pour des comprimés ayant une charge initiale en vitamine plus importante, cela liée à une augmentation de la porosité de la matrice avec l’épuisement graduel de la vitamine. Concernant la technique de préparation, un taux de sortie beaucoup plus faible dans le cas des comprimés préparés par extrusion en phase chauffante préalable, est mesuré, dû à un emprisonnement de la vitamine par la matrice fondue. A partir de ces observations et des connaissances sur les matrices lipidiques, un modèle basé sur les lois de diffusion de Fick et sur la considération de la coexistence d’une partie du principe actif sous forme dissoute ou non dissoute a été élaboré. Ce modèle permet la prédiction de la quantité de vitamine libérée au cours du temps en fonction de l’impact de la composition, de la technique de préparation et de la taille du système. Ces simulations in-silico sont d’une grande aide pour permettre d’accélérer la production de comprimés à base de Compritol 888. Dans le cas de systèmes multiparticulaires, et encore plus dans le cas de formes enrobées, des modèles mathématiques peuvent également être établis mais montrent une complexité plus grande, notamment due à la membrane polymérique. Dans cette optique, le développement de nouveaux outils pour caractériser les systèmes est primordial. Dernièrement la technologie Terahertz voit son potentiel comme nouvel outil dans la caractérisation de systèmes enrobés croissant. Son emploi dans la détection de différence de taille et d’uniformité de films polymériques d’enrobage pour des systèmes multicouches a été réalisé sur des granules de tailles conventionnelles (1mm de diamètre). Un premier enrobage de metoprolol succinate a été réalisé sur des noyaux de sucre, suivi d’un enrobage permettant le contrôle de la fuite du principe actif à base d’un mélange de Kollicoat SR :Kollicoat IR. Des granules avec différentes tailles d’enrobage ont été étudiées par Terahertz. Une taille homogène de la couche de principe actif pulvérisée a été montré dans tous les types de pellets ; alors qu’une taille croissante de l’enrobage polymérique 46 µm, 71 µm et 114 µm a pu être appréhendée. Ces résultats, mis en corrélation avec les méthodes de dissolution traditionnelles, permettront le développement d’une formule prédisant les cinétiques de libération à partir de la lecture non destructive de l’épaisseur d’enrobage par Térahertz.[...]
Development of new galenic devices needs series experiments with variation of number parameters. For industrial, it’s a lost in time and money. Food and Drug Administration initiated since several years, Process Analytical Technology (PAT) as a tool to analyze and control pharmaceutical process. These tools can be helpful to determine drug release mechanism and allow application of mathematical model to predict drug release kinetics. One objective of this work is to develop a mechanistically realistic mathematical model allowing for the quantification of vitamin release from Compritol 888 (glyceryl dibehenate NF)-based matrix tablets, prepared either by direct compression or via hot-melt extrusion/grinding/compression. Nicotinic acid has been used as highly soluble drug in surrounding medium. Dissolution studies show vitamin release rates increased with increasing initial niacin content, due to the increased matrix porosity upon vitamin depletion. In all cases, niacin release from tablets prepared via hot-melt extrusion was slower than from tablets prepared by direct compression, due to more intense embedding of the vitamin within the lipid. Importantly, a numerical model based on Fick’s law of diffusion and considering the co-existence of dissolved and non-dissolved vitamin could successfully be used to quantify vitamin release from both types of tablets, irrespective of the initial niacin loading and tablet size. In-silico simulations can be very helpful to accelerate product optimization of Compritol 888-based matrices, saving development time and costs. For multiparticulates systems, and more again for coated forms, mathematical models are more complexes. In this goal, development of new tools to characterize devices is primordial. Technology Terahertz offers an interesting potential. This technique can be used to detect difference in size and uniformity for polymeric film from multilayer pellets of 1 mm diameter. Pellets consisting of a sugar starter core and a metoprolol succinate layer were coated with a Kollicoat® SR: Kollicoat® IR polymer blend. Pellets with several coating thickness are studied. No drug layer thickness difference between batches was observed, and the average coating thicknesses were 46 µm, 71 µm and 114 µm, for the different batches. Terahertz results compared with experimental data from dissolution methods, allow predicting coating thickness results correlated with the subsequent drug release behavior. Multiparticulates systems have important interest: they allow avoiding “dose dumping”. Dose dumping is described as an unintended, rapid drug release in a short period of time of the entire amount or a significant fraction of the drug contained in a modified release dosage form (Meyer, 2005). This phenomenon can be observed in the case of ethylcellulose-based devices in presence with ethanol rich-media. Recently, ethylcellulose:guar gum blend have been reported to provide ethanol-resistant drug release kinetics from coated dosage forms. Theophylline matrix pellets were coated with ethylcellulose: guar gum blends. These granules show no change in drug release profiles upon contact with medium containing 40% of ethanol (v/v). This is because the ethanol insoluble guar gum effectively avoids undesired ethylcellulose dissolution in ethanol-rich bulk fluids. However, so far the importance of crucial formulation parameters, including the minimum amount of guar gum to be incorporated and the minimum required guar gum viscosity, remains unclear. It was found that more than 5% guar gum (referred to the total polymer content) must be incorporated in the film coating and that the apparent viscosity of a 1% aqueous guar gum solution must be greater than 150 cPs to provide ethanol-resistance. [...]

The use of composting is expected to increase dramatically due to its economic and environmental benefits. For public health protection, regulators and licensing authorities are requesting risk assessments to be conducted prior to the development and operation of composting. Significant amounts of microrganisms can be aerosolised and transported by winds to points of exposure. However, the source term factors that influence their release and their dispersal are not fully understood. In this thesis a method to measure viable bioaerosols emission rates from static compost pile surfaces and during the agitation of compost was developed. The factors that influence the emission of bioaerosols from compost piles of different ages and during different agitation activities were evaluated. A wind tunnel analysis was successfully used to measure the surface flux bioaerosols emission rate. Newly estimated emission rates from various source terms were then modelled to produce source depletion curves. The surface emission flux of a static pile was estimated to be 102 to 104cfu/m2/s for both A. fumigatus and actinomycetes. The turning of compost releases the highest bioaerosols concentration range from 104 to 108cfu/s compared with the shredding and screening. The turning of an early stage compost windrow emitted the highest amount of bioaerosols. This study introduces a new method for quantifying bioaerosols dispersal, thus improving the risk assessments required for environmental permitting.

Magnocellular neurones (MCNs) are capable of secreting vasopressin and oxytocin from the somato-dendritic compartment, which can occur independently to secretion from nerve terminals. One hypothesis of the mechanism that regulates this differential release is that dendrites utilise different vesicle pools compared to those found in terminals. Little is known for the function of neuronal dendrites, especially the mechanism for peptide release. One theory is that vesicles stored in dendrites are non-released vesicles ready for recycling or degradation. Immunofluorescent labelling was performed on hypothalamic slices of the transgenic rat where enhanced green fluorescent protein (eGFP) was tagged to vasopressin. Lysosomes were detected by the lysosome-associated membrane protein LAMP1. Correlation analysis of LAMP1 labelling and VP-eGFP had shown that localisation of lysosomes in dendrites is positively correlated to loci of high vasopressin expression. This suggests active degradation of vesicles in dendrites. It is not known whether preferential release of peptides occurs along the profile of dendrites. Experiments were carried out using a temperature block to block exit of vesicles from the Golgi apparatus. Release of the temperature block triggered release of a wave of newly synthesised vesicles from the Golgi apparatus. Measurement of the fluorescent intensity of VP-eGFP showed that preferential release of peptides does not occur along the profile of dendrites. I have also utilised confocal live cell imaging to study the dynamics of dendritic vasopressin release using VP-eGFP slice explants. Experiments using high potassium stimulation showed significant increase in the release of vasopressin after priming with thapsigargin (intracellular calcium mobiliser), in accordance to in vitro release and microdialysis studies. These results demonstrate that live cell imaging can be achieved in magnocellular neurons, providing a robust model system in the study of dendritic peptide release. Large dense core vesicles (LDCVs) in other cell types such as bovine adrenal chromaffin cells were shown to segregate according to vesicle age, suggesting that vesicle age is an important factor in the regulation of peptide release. Whether vesicles of different age groups exist in magnocellular dendrites is not known. Thus, biolistic transfection with exogenous fluorescent proteins for expression under temporal control was carried out. However, low transfection rate in magnocellular neurones and the high background fluorescence caused by scattered gold particles used as bullets for transfection deemed this method inappropriate for the purpose of imaging vesicles. Hence, development of an adenoviral transduction system was employed. By using an inducible adenovirus gene construct coupled with a fluorescent reporter gene, it is possible to visualise vesicle pool segregation under different experimental conditions. Subcloning of a red fluorescent construct tagged to ppANF was tested on PC12 cells to show targeting of fluorescence expression to LDCVs. Successful production of an inducible adenoviral DNA with the red fluorescent construct insert was confirmed by PCR and DNA sequencing. Whilst the generation of viral particles is still to be achieved, successful production of the virus will be an invaluable system for inducible gene expression in neurones.

Like all other viruses, a successful egress of functional particles from infected cells is a prerequisite for foamy virus (FV) spread within the host. The budding process of FVs involves steps, which are shared by other retroviruses, such as interaction of the capsid protein with components of cellular vacuolar protein sorting (Vps) machinery via late domains identified in some FV capsid proteins. Additionally, there are features of the FV budding strategy quite unique to the spumaretroviruses. This includes secretion of non-infectious subviral particles and a strict dependence on capsid-glycoprotein interaction for release of infectious virions from the cells. Virus-like particle release is not possible since FV capsid proteins lack a membrane-targeting signal. It is noteworthy that in experimental systems, the important capsid-glycoprotein interaction could be bypassed by fusing heterologous membrane-targeting signals to the capsid protein, thus enabling glycoprotein-independent egress. Aside from that, other systems have been developed to enable envelopment of FV capsids by heterologous Env proteins. In this review article, we will summarize the current knowledge on FV budding, the viral components and their domains involved as well as alternative and artificial ways to promote budding of FV particle structures, a feature important for alteration of target tissue tropism of FV-based gene transfer systems.

Thesis: S.B., Massachusetts Institute of Technology, Department of Mechanical Engineering, 2014.
Cataloged from PDF version of thesis.
Includes bibliographical references (page 41).
The failure of a dam can cause disastrous consequences, thus understanding the nature of a dam break is of utmost importance. A model of a dam break was built and used to profile the resulting wave. The gate release was characterized to check for consistency, maximum velocity, and it's profile. Matlab code was created to analyze both the gate speed and the wave velocity. The maximum velocity was 1503.2 cm/s and there a 30% deviation at most.The wave velocity was found to increase as the water reservoir height was increased. An equation was derived that had a 0.96 correlation coefficient thus proving that the relationship between velocity and reservoir height was accurate. Further research can be done using a cantilevered plate downstream of the dam break to analyze the forces generated.
by Juliana Wu.
S.B.

Cardiovascular disease (CVD) is one of the main causes of death in western society. Platelet activation, thrombus formation and plaque rupture are all central events in the pathogenesis of acute coronary syndromes, therefore therapies targeted at controlling platelet numbers and aggregation are likely to be beneficial in the treatment of CVD. Megakaryocytes (MKs) which are the precursors to platelets are an ideal target for these therapies, however the intrinsic factors that regulate the production and shedding of platelet precursors are poorly understood. Recent studies identified that MKs express functional NMDA-type glutamate receptors similar to those found in the CNS and that antagonism of these receptors prevents normal MK differentiation and platelet function. This thesis investigates glutamate signalling within MKs further, focusing on the glutamate release capability of MK cells and the mechanisms involved. Using molecular and cellular techniques it was demonstrated that MK cells expressed numerous regulatory proteins required for vesicular glutamate release, including core SNARE proteins, VAMP, SNAP-23 and syntaxin; specific glutamate-loading vesicle proteins, VGLUTI and VGLUT2; and glutamate transporters, EAATI and EAAT2. Active vesicle recycling was observed in MK cells using a fluorescent reporter and an enzyme-linked fluorimetric assay confirmed that MK cells constitutively released glutamate and that glutamate release levels increased significantly following MK differentiation. Transient transfection of the human cell line MEG-Ol with tetanus toxin, which disables vesicle recycling, induced a 30% decrease (P