In product pricing and reserving, actuaries are often required to make predictions of future death rates. In the past, this has been performed by using deterministic improvement scales that give only a single mortality trajectory. However, there is enormous likelihood that future death rates will turn out to be different from the projected ones, and so a better assessment of longevity risk would be one that consists of both a mean estimate and a measure of uncertainty. Such assessment can be performed using a stochastic mortality model, which is the core of this thesis. The Lee-Carter model is one of the most popular stochastic mortality models. While it does an excellent job in mean forecasting, it has been criticized for providing overly narrow prediction intervals that may have underestimated uncertainty. This thesis mitigates this problem by relaxing the assumption on the distribution of death counts. We found that the generalization from Poisson to negative binomial is equivalent to allowing gamma heterogeneity within each age-period cells. The proposed extension gives not only a better fit, but also a more conservative prediction interval that may reflect better the uncertainty entailed. The proposed extension is then applied to the construction of mortality improvement scales for Canadian insured lives. Given that the insured lives data series are too short for a direct Lee-Carter projection, we build an extra relational model that could borrow strengths from the Canadian population data, which covers a far longer period. The resultant scales consist of explicit measures of uncertainty. The prediction of the tail of a survival distribution requires a special treatment due to the lack of high quality old-age mortality data. We utilize the asymptotic results in modern extreme value theory to extrapolate death probabilities to the advanced ages, and to statistically determine the age at which the life table should be closed. Such technique is further integrated with the Lee-Carter model to produce a stochastic analysis of old-age mortality, and a prediction of the highest attained age for various cohorts. The mortality models we considered are further applied to the valuation of mortality-related financial products. In particular we investigate the no-negative-equity-guarantee that is offered in most fixed-repayment lifetime mortgages in Britain. The valuation of such guarantee requires a simultaneous consideration of both longevity and house price inflation risk. We found that house price returns can be well described by an ARMA-EGARCH time-series process. Under an ARMA-EGARCH process, however, the Black-Scholes formula no longer applies. We derive our own pricing formula based on the conditional Esscher transformation. Finally, we propose some possible hedging and capital reserving strategies for managing the risks associated with the guarantee.

In product pricing and reserving, actuaries are often required to make predictions of future death rates. In the past, this has been performed by using deterministic improvement scales that give only a single mortality trajectory. However, there is enormous likelihood that future death rates will turn out to be different from the projected ones, and so a better assessment of longevity risk would be one that consists of both a mean estimate and a measure of uncertainty. Such assessment can be performed using a stochastic mortality model, which is the core of this thesis. The Lee-Carter model is one of the most popular stochastic mortality models. While it does an excellent job in mean forecasting, it has been criticized for providing overly narrow prediction intervals that may have underestimated uncertainty. This thesis mitigates this problem by relaxing the assumption on the distribution of death counts. We found that the generalization from Poisson to negative binomial is equivalent to allowing gamma heterogeneity within each age-period cells. The proposed extension gives not only a better fit, but also a more conservative prediction interval that may reflect better the uncertainty entailed. The proposed extension is then applied to the construction of mortality improvement scales for Canadian insured lives. Given that the insured lives data series are too short for a direct Lee-Carter projection, we build an extra relational model that could borrow strengths from the Canadian population data, which covers a far longer period. The resultant scales consist of explicit measures of uncertainty. The prediction of the tail of a survival distribution requires a special treatment due to the lack of high quality old-age mortality data. We utilize the asymptotic results in modern extreme value theory to extrapolate death probabilities to the advanced ages, and to statistically determine the age at which the life table should be closed. Such technique is further integrated with the Lee-Carter model to produce a stochastic analysis of old-age mortality, and a prediction of the highest attained age for various cohorts. The mortality models we considered are further applied to the valuation of mortality-related financial products. In particular we investigate the no-negative-equity-guarantee that is offered in most fixed-repayment lifetime mortgages in Britain. The valuation of such guarantee requires a simultaneous consideration of both longevity and house price inflation risk. We found that house price returns can be well described by an ARMA-EGARCH time-series process. Under an ARMA-EGARCH process, however, the Black-Scholes formula no longer applies. We derive our own pricing formula based on the conditional Esscher transformation. Finally, we propose some possible hedging and capital reserving strategies for managing the risks associated with the guarantee.

Mini-matrix multiple unit dosage forms (MUDFs) of diclofenac sodium and S(+) ibuprofen have been prepared. Normal tabletting techniques were used to form the mini-matrices prior to their enclosure in hard gelatin capsules. Four natural hydrophilic gums, namely xanthan, karaya, locust bean and carrageenan gums as well as hydroxypropyl methylcellulose (HPMC) were used as the principle release-retarding agents. Various excipients - lactose, Encompress®, cellulose acetate phthalate (CAP), Veegum F® and Avicel PH101® - were added in different proportions to further modify drug release. The diclofenac sodium mini-matrices (4.5 mm in diameter) were produced by the wet granulation method. The release profiles from several encapsulated minimatrices in phosphate buffer solution (pH 7.0) showed that xanthan, karaya and locust bean gums could sustain the release of diclofenac sodium while the carrageenan gum did not produce a satisfactory sustaining effect. The rank order of decreasing swelling rate in both axial and radial dimensions was xanthan > karaya > locust bean gum and each of these gums showed almost Fickian swelling behaviour. The solvent penetration rates were consistent with the swelling rates. However, the order of decreasing drug release and erosion rates was locust bean> xanthan > karaya gum. For each of these gums, the release behaviour was anomalous indicating that both Fickian drug diffusion and polymer relaxation were involved in the release process. The dominant mechanism depended on the nature and content of the gum, as well as the stage in the dissolution period. The study involving xanthan gum showed that the diclofenac sodium release rate declined linearly with a progressive increase in the gumcontent, without changing the release behaviour. However, for high drug: xanthan gum ratio (2:1), the release kinetics changed to Super Case II. Solubility differences between the excipients did not affect the release rate, but increasing proportions of each excipient produced a faster release rate with the release mechanism changing from anomalous to Case II and then to Super Case II transport. Mini-matrices containing HPMC produced faster drug release than those containing the three natural gums. There was no synergistic effect between xanthan and locust bean gums on the release of diclofenac sodium from mini-matrices. Variation in the stirring speed (used in the dissolution apparatus) and matrix volume had little effect on drug release, whereas the pH of the dissolution medium greatly affected the release of diclofenac sodium. Following on from the studies involving diclofenac sodium, xanthan and karaya gums were used to produce mini-matrices of S(+) ibuprofen. Excipients with good compressibility characteristics such as lactose, Encompress® and Avicel PH101® were needed in the formulations. At pH 7, higher drug release rates were obtained with karaya gum (Super Case II mechanism) compared with xanthan gum (anomalous behaviour). Solubility differences between the excipients slightly affected the release rate. Compression forces (11 - 26 kN) slightly affected the crushing strength. The minimatrices were relatively stable to variation in temperature (5 - 37°C) and relative humidity (10 - 75%) over a 2 month time period. These studies have shown that near zero-order release of diclofenac sodium and S(+) ibuprofen can be achieved using encapsulated mini-matrices formulations. The release mechanisms and release rates can be adjusted by variation of the type and content of gums and/or excipients.

Les mini-granules enrobées offrent un grand potentiel pour la libération contrôlée de médicament par voie orale. Cependant, les mécanismes de libération impliqués ne sont pas toujours élucidés et compris. Ainsi, l’impact de certains paramètres de formulation peut être surprenant. Par exemple, il a été démontré dans ce travail :- La libération du propranolol HCl à partir de mini-granules enrobées avec du Kollicoat SR est plus lente si les mini-granules sont composées de noyaux de sucre comparé à des noyaux de cellulose microcristalline (CMC).Généralement, la tendance inverse est observée, car les noyaux de sucre ont une activité osmotique attirant plus rapidement l’eau à l’intérieur du système et entrainant ainsi, une dissolution et diffusion de la substance active. Ce résultat inattendu est dû à une association de 2 phénomènes : (i) l’effet plastifiant dû au sucre sur le film de Kollicoat SR et (ii) la diminution de la solubilité de cette SA dans le milieu de dissolution en présence de sucre dissous.De plus, le Kollicoat SR 30 D [dispersion aqueuse de poly(vinyl pyrrolidone)] offre des possibilités intéressantes de formulation par sa haute flexibilité et ses propriétés mécaniques stables. En revanche, les mini-granules composées de noyaux de sucre ont tendance à gonfler de par le cumul de l’activité osmotique du noyau et de la SA jusqu’à l’apparition de « cracks », révélés par des images obtenues par micro tomographie à rayons X.- Lorsqu’on augmente la quantité en propranolol HCl dans le système, la cinétique de libération est augmentée, particulièrement avec les mini-granules composées de noyaux de CMC.L’opposé est souvent constaté car accroitre la quantité de SA nécessite un plus grand apport en eau afin de pouvoir tout dissoudre. Les mini-granules à base de CMC présentent probablement des « cracks » malgré un faible gonflement du système, et sont accentués par l’augmentation de la concentration en propranolol HCl.En conclusion, des nouvelles connaissances sur les mécanismes de libération à partir de mini-granules enrobées avec du Kollicoat SR ont été apportées et l’importance du type de SA et la nature du noyau composant le système ont été élucidées.- Dans une deuxième partie, des mini-granules enrobées avec un mélange de polymère (Aquacoat ECD et Eudragit NM 30 D) ont été formulées dans le but de libérer la diprophylline, SA modèle, par diffusion à travers le film de polymère et de pouvoir modéliser sa cinétique à partir de modèles mathématiques. / Polymer coated pellets offer a great potential for control drug delivery system. Nevertheless, the underlying drug release mechanisms can be complex and are not fully understood. Thus, the impact of formulation parameters can be surprising. For example, it has been demonstrated during this thesis that:- The release of propranolol HCl was slower from sugar-based pellets coated with Kollicoat SR compared to microcrystalline cellulose (MCC)-based pellets.Generally, the opposite was observed because the sugar cores are osmotically active attracting more and more water into the system leading to a fast dissolution and diffusion of the drug, especially with high water-soluble drug. This unexpected result is due to a combination of two phenomena: (i) The plasticizing effect of sugar for the film coating and (ii) Decrease in drug solubility in the release medium due to the presence of co-dissolved sugar.In addition, Kollicoat SR 30 D [an aqueous dispersion of poly(vinyl acetate) also containing small amounts of poly(vinyl pyrrolidone) and sodium lauryl sulfate] is a very interesting polymer owing to its high flexibility and stable mechanical properties. However, sugar-based pellets tend to swell by the osmotic pressure created by the high water-soluble API and the sugar until crack formation, clearly visible on the images obtained by X-ray micro tomography.- Propranolol HCl release in phosphate buffer pH 7.4 increases by increasing the drug loading into the system, especially from MCC-based pellets.The opposite was often observed since the amount of water within the drug reservoir might not be sufficient to dissolve all drug. MCC-based pellets likely presented also cracks despite a low swelling of the system, accentuated by the increase of propranolol HCl concentration.To conclude, new insights on the underlying drug release mechanisms from Kollicoat SR coated pellets were provided. The importance of the type of drug and the nature of starter cores were elucidated.- In the second part, diprophylline loaded pellets coated with a polymer blend composed of Aquacoat ECD and Eudragit NM were prepared in order to control the drug release only by diffusion through the intact polymeric film and to predict the drug kinetics using mathematical models.

Hold down release mechanisms (HDRMs) are used for tightly attaching segments of bodies together when it is desired to release them rapidly at some point. When transporting sensitive payloads on launch vehicles, the challenge arises of releasing the fastened segments of the spacecraft without risking damage to the costly equipment. Non-explosive HDRMs are favourable from a safety perspective as there is a lower risk of producing potentially destructive shock-waves throughout the structure.  One variant of a non-explosive HDRM uses a so called 'split spool initiator'. This initiator can only be used once in the actuator mechanism and to reuse the HDRM the initiator must be replaced. The purpose of this thesis is to design an improved split spool initiator which can be reusable while conserving the functionality aspects of the existing design. To achieve this, different ideas were considered and ultimately a solution using shape memory alloys (SMAs) was explored. A prototype was constructed to demonstrate the functionality of the design and simulations are done to determine the forces acting on different parts of the mechanism. / Hold down release-mekanismer (HDRM) används för att säkert kunna fästa samman delar av strukturer för att sedan kunna lossa dessa vid rätt tillfälle. När det transporteras känslig last på exempelvis rymdfarkoster uppkommer utmaningen att göra så på ett sätt som inte riskerar att skada den ofta dyra utrustningen. Det finns en mängd olika HDRM, dessa kan delas upp i två typer som är icke explosiva release-mekanismer och pyrotekniska release-mekanismer. Icke explosiva release-mekanismer har en fördel över pyrotekniska som är att de inte producerar potentiellt destruktiva chock-vågor som sprids genom strukturen. En typ av icke-explosiva release-mekanismer är den så kallade split spool-initieraren. Denna kan endast användas en gång när fästelementet är aktiverat och för att kunna använda fästelementet igen måste hela initieraren bytas ut. Syftet med denna studie har varit att att designa en förbättrad split spool-initierare som är återanvändbar, medan funktionaliteten hos den ursprungliga designen är bevarad. För att åstadkomma detta övervägdes olika idéer och slutligen valdes en lösning som använder minnesmetaller eller Shape memory alloys på engelska (SMA). En prototyp konstruerades för att demonstrera funktionaliteten hos designen. Simuleringar gjordes även för att bestämma krafter som agerade på split spool-strukturen och för att få en överblick över spänningsfördelningen genom initieraren.