Trois dérivés d'amino acides sont reconnus d'une manière stéréo sélective par l'albumine du sérum bovin. Cette propriété a été observée dans le cas de la phosphatase alcaline de tissu non spécifique, (TNAP). Des inhibiteurs agissant à trois niveaux distincts sur les processus de minéralisation ont été cherchés: 1) TNAP ; 2) Formation de l'hydroxyapatite (HA); 3) Vésicules maticielles (VMs). Nous avons trouvé que des dérivés de benzothiophènes et de tétramisoles, solubles dans l'eau, sont des inhibiteurs spécifiques de TNAP. Un modèle qui permet de produire du HA, a été développé et a confirmé que les nucléotides sont des inhibiteurs de formation de HA. Nous avons montré que le médicament anti-rhumatisme sinomenine, n'ayant aucun effet sur le TNAP, ainsi que la théophylline ralentissaient tous les deux la formation de HA induits par les VMs. Ces modèles de minéralisation présentent un grand potentiel lors du criblage de médicaments pour le traitement de l'ostéoarthrose

Dissertation (Ph.D.)--University of South Florida, 2007. / Title from PDF of title page. Document formatted into pages; contains 141 pages. Includes vita. Includes bibliographical references.

The Electrospray (ES) technique is a promising particle generation method for drug delivery due to its capabilities of producing monodisperse PLGA composite particles with unique configurations and high drug encapsulation efficiency. In the dissertation work, the coaxial dual capillary ES was used to generate drug-loaded core-shell PLGA particles to study the effects of particle filling materials, drug loading locations and particle shell thicknesses on the resultant in vitro release behaviors of the hydrophilic and/ or hydrophobic model drugs. Through release profile characterization of drug-loaded PLGA particles (particle size: 400 nm and 1 μm), it was confirmed that the co-encapsulation of Budesonide (BUD, the hydrophobic small-molecule model drug) and Theophylline (THY, the hydrophilic small-molecule model drug) in the particle cores is the most effective drug loading strategy for extended release of the fixed combined BUD and THY. Particles composed of PLGA fillers with lower molecular weights and with greater shell layer thicknesses could release THY in a well controlled fashion. On the other hand, a slower release rate of Bovine Serum Albumin (BSA, the protein model drug) from PLGA particles with greater shell thickness was also observed. Sequential release of BSA and Paclitaxel (PTX, the hydrophobic small-molecule anti-cancer model drug) was achieved by the 400-nm PLGA (Mw: 7,000-17,000 g/mol, LA/GA: 50/50) particles with potential biopharmaceutical applications in cancer therapy.

This work focuses on the physical properties and crystallization of theophyline co-crystals. Co-crystals of theophylline with oxalic acid, glutaric acid and maleic acid have been investigated. The DSC curves of these co-crystals show that their first endothermic peaks are all lower than the melting temperature of theophylline. The decomposition temperature of theophylline – oxalic acid co-crystal is at about 230 °C, determined by DSC together with TGA. After decomposition, the remaining theophylline melts at about 279 °C, which is higher than the known melting temperature of theophylline, suggesting a structure difference, ie. a new polymorph may have been formed. The formation of hydrogen bonds in theophylline – oxalic acid co-crystal was investigated by FTIR. Changes of FTIR peaks around 3120 cm-1 reflects the hydrogen bond of basic N of theophylline and hydroxyl H of oxalic acid. The solubility of theophylline – oxalic acid co-crystal and theophylline – glutaric acid co-crystal was determined in 4:1 chlroform – methanol and in pure chloroform respectively. At equilibrium with the solid theophylline – oxalic acid co-crystal, the theophylline concentration is only 60 % of the corresponding value for the pure solid theophylline. At equilibrium with the solid theophylline – glutaric acid co-crystal, the theophylline concentration is at least 5 times higher than the corresponding value for the pure solid theophylline. Two phases of theophylline were found during the solubility determination. In the chloroform – methanol mixture (4:1 in volume ratio) the solubility of the stable polymorph of theophylline is found to be about 14 % lower than that of the metastable phase. Various aspects of the phase diagram of theophylline – oxalic acid co-crystal was explored. Theophylline – oxalic acid co-crystal has been successfully prepared via primary nucleation from a stoichiometric solution mixture of the two components in chloroform – methanol mixture. By slurry conversion crystallization, the co-crystal can be prepared in several solvents, and yield and productivity can be significantly increased. Theophylline – glutaric acid can be successfully prepared via both co-grinding of the two components and slow evaporation with seeding. / QC20100608

<p>This work focuses on the physical properties and crystallization of theophyline co-crystals. Co-crystals of theophylline with oxalic acid, glutaric acid and maleic acid have been investigated.</p><p>The DSC curves of these co-crystals show that their first endothermic peaks are all lower than the melting temperature of theophylline. The decomposition temperature of theophylline – oxalic acid co-crystal is at about 230 °C, determined by DSC together with TGA. After decomposition, the remaining theophylline melts at about 279 °C, which is higher than the known melting temperature of theophylline, suggesting a structure difference, ie. a new polymorph may have been formed. The formation of hydrogen bonds in theophylline – oxalic acid co-crystal was investigated by FTIR. Changes of FTIR peaks around 3120 cm^-1 reflects the hydrogen bond of basic N of theophylline and hydroxyl H of oxalic acid. The solubility of theophylline – oxalic acid co-crystal and theophylline – glutaric acid co-crystal was determined in 4:1 chlroform – methanol and in pure chloroform respectively. At equilibrium with the solid theophylline – oxalic acid co-crystal, the theophylline concentration is only 60 % of the corresponding value for the pure solid theophylline. At equilibrium with the solid theophylline – glutaric acid co-crystal, the theophylline concentration is at least 5 times higher than the corresponding value for the pure solid theophylline. Two phases of theophylline were found during the solubility determination. In the chloroform – methanol mixture (4:1 in volume ratio) the solubility of the stable polymorph of theophylline is found to be about 14 % lower than that of the metastable phase. Various aspects of the phase diagram of theophylline – oxalic acid co-crystal was explored.</p><p>Theophylline – oxalic acid co-crystal has been successfully prepared via primary nucleation from a stoichiometric solution mixture of the two components in chloroform – methanol mixture. By slurry conversion crystallization, the co-crystal can be prepared in several solvents, and yield and productivity can be significantly increased. Theophylline – glutaric acid can be successfully prepared via both co-grinding of the two components and slow evaporation with seeding.</p> / QC20100608

This dissertation has focused on the solid-state characterization of different co-crystal system as well as the effect of co-crystallization of these systems on pharmaceutical dosage form performance. Urea/ 2-MB, caffeine/ malonic acid, caffeine/ oxalic acid and theophylline/ malonic acid co-crystals were prepared using co-grinding- and co-precipitation techniques. In addition, the synthesis of co-crystals through two novel methods has been demonstrated. This includes compaction and convection mixing. The solid-state characterization of the co-crystals has been carried out using XRPD, Raman spectroscopy, DSC, TGA, hot-stage microscopy and SEM. After preparation of co-crystals, tablets have been produced from co-ground-, co-precipitated-, and physical mixtures using Compaction Studies Press (Kaleva), and the data were recorded to compare between the different mixtures, regarding compactibilty, compressibility and deformational properties. The DSC results showed that the physical mixtures of all systems, formed co-crystals during heating process. For systems of urea/ 2-MB, caffeine/ malonic acid and theophylline/ malonic acid, the co-ground mixture produced tablets with higher tensile strength compared with either co-precipitated or physical mixture. However, for caffeine/ oxalic acid system, the tensile strengths of compacts produced from the physical mixture were greater than those obtained from either co-ground or co-precipitated mixtures. The Heckel data suggested that urea/ 2-MB, caffeine/ malonic acid and theophylline/ malonic acid systems are Type 1 materials, as an extensive linearity during compression was indicative of a plastic deformation mechanism, while the caffeine/ oxalic acid system was Type 2 materials. However, the co-precipitated mixture of urea/ 2-MB system was the least compressible, as it possessed the greatest value of yield pressure (85 MPa) and the highest elastic recovery (7.42%). The co-precipitated mixture of both of caffeine/ malonic acid and theophylline/ malonic acid systems was the most compressible with small yield pressure values of (44 & 80 MPa) and elastic recovery of (7.2% & 6.56%), respectively. The co-ground mixture of caffeine/ oxalic acid possessed the highest value of yield pressure (166 MPa) and thus the lowest compressibility among other mixtures. Furthermore, the addition of microcrystalline cellulose and α-lactose monohydrate has affected the crystallinity as well as the tableting properties of the co-crystals. After the addition of excipients, the tensile strength of compacts was about 2 times higher than any other mixture. Finally, urea/ 2-MB and caffeine/ malonic acid co-crystals were successfully synthesized through convection mixing and compaction.

Le but de ce travail était d'étudier le comportement des cristaux de théophylline lors de la déshydratation statique en monocouche dans différentes conditions hygrothermiques et le comportement du même produit lors de la déshydratation séchage en lit agité dans un séchoir par contact sous vide dans des conditions hygrothermiques semblables. Tout d'abord, la forme hydratée et les formes déshydratées de la théophylline ont été identifiées par DSC, ATG et DRXP. Ensuite, des essais gravimétriques statiques à température et humidité relative constantes ont été effectués et les évolutions de teneur en eau au cours du temps ont été enregistrées à des températures de 20 à 80 °C et des humidités relatives de 4 à 50%. Les données à l'équilibre thermodynamique ont été utilisées pour tracer les isothermes de désorption et établir le diagramme de phase solide-solide de la théophylline. Enfin, les cinétiques de déshydratation ont été étudiées. Il a été constaté que la constante de vitesse de déshydratation augmente exponentiellement avec la température et diminue de façon exponentielle avec l'humidité relative. Un modèle semi-empirique permettant la prédiction de l'évolution dans le temps de la teneur en eau du produit pour différentes conditions opératoires a été développé. Dans la seconde partie du travail, il a été d'abord démontré que la SPIR couplée avec la régression PLS permet de suivre en ligne et in situ la composition exacte du mélange des différentes formes de la théophylline (et d'eau) pendant le séchage. Ensuite, l'influence des paramètres de fonctionnement (température et l'activité de l'eau) sur les cinétiques de transformation de l'état solide a été étudiée. Il a été observé que la déshydratation commence d'abord par la formation de la forme anhydre métastable puis, après un temps de latence, continue par la formation de la forme anhydre stable. Il s'est avéré aussi que la température a été le principal facteur contrôlant la vitesse globale du procédé, mais aussi la teneur finale de la forme anhydre stable et de la forme métastable, ceci étant valable pour le séchoir étudié et pour les conditions opératoires considérées. Finalement, un modèle semi-empirique permettant la simulation de l'état du produit (température, teneur en eau, teneur en forme hydratée, anhydre métastable et stable) au cours du temps pour différentes conditions opératoires du séchage (pression dans la cuve et température du fluide caloporteur) a été proposé / The aim of this work was to investigate the dehydration process of a single static layer of theophylline's crystals under different hygrothermal conditions and the dehydration-drying process of a stirred bed of theophylline in a vacuum contact dryer in nearly the same hygrothermal conditions. First of all, the hydrated and dehydrated forms of theophylline were identified using DSC, TGA and PXRD devices. Next, the static gravimetric experiments at constant temperature and relative humidity were carried out and the water content evolutions with time were recorded at temperatures from 20 to 80°C and humidities from 4 to 50%. Then, the thermodynamic equilibrium data were reported as desorption isotherms and solid-solid phase diagrams. Finally, the dehydration kinetics were analyzed. The dehydration rate constant was found to increase exponentially with temperature and to decrease exponentially with relative humidity. A simple semi-empirical model allowing for prediction of the product water content time evolution time for different processing parameters was developed. In the second part of the work, it was first proven that NIRS coupled with PLS regression enabled to monitor inline and in-situ the exact composition of the mixture of different forms of theophylline (and of water) during drying. Second, the influence of operating parameters (temperature and water activity) on the kinetics of solid state transformations was investigated. It was observed that the dehydration begun by the formation of the metastable anhydrate and, after a time delay, continued by the formation of the stable one. It was also pointed out that the temperature was the main process factor controlling not only the overall process rate but also the final contents of the stable and metastable anhydrates, this observation being valid for the considered dryer and for the considered operating conditions. Finally, a semi-empirical model allowing for simulation of the product state (temperature, hydrate content, metastable and stable anhydrate contents and water content) time evolution for different processing parameters (pressure in the vessel and temperature of the heating fluid) was proposed

This dissertation has focused on the solid-state characterization of different co-crystal system as well as the effect of co-crystallization of these systems on pharmaceutical dosage form performance. Urea/ 2-MB, caffeine/ malonic acid, caffeine/ oxalic acid and theophylline/ malonic acid co-crystals were prepared using co-grinding- and co-precipitation techniques. In addition, the synthesis of co-crystals through two novel methods has been demonstrated. This includes compaction and convection mixing. The solid-state characterization of the co-crystals has been carried out using XRPD, Raman spectroscopy, DSC, TGA, hot-stage microscopy and SEM. After preparation of co-crystals, tablets have been produced from co-ground-, co-precipitated-, and physical mixtures using Compaction Studies Press (Kaleva), and the data were recorded to compare between the different mixtures, regarding compactibilty, compressibility and deformational properties. The DSC results showed that the physical mixtures of all systems, formed co-crystals during heating process. For systems of urea/ 2-MB, caffeine/ malonic acid and theophylline/ malonic acid, the co-ground mixture produced tablets with higher tensile strength compared with either co-precipitated or physical mixture. However, for caffeine/ oxalic acid system, the tensile strengths of compacts produced from the physical mixture were greater than those obtained from either co-ground or co-precipitated mixtures. The Heckel data suggested that urea/ 2-MB, caffeine/ malonic acid and theophylline/ malonic acid systems are Type 1 materials, as an extensive linearity during compression was indicative of a plastic deformation mechanism, while the caffeine/ oxalic acid system was Type 2 materials. However, the co-precipitated mixture of urea/ 2-MB system was the least compressible, as it possessed the greatest value of yield pressure (85 MPa) and the highest elastic recovery (7.42%). The co-precipitated mixture of both of caffeine/ malonic acid and theophylline/ malonic acid systems was the most compressible with small yield pressure values of (44 & 80 MPa) and elastic recovery of (7.2% & 6.56%), respectively. The co-ground mixture of caffeine/ oxalic acid possessed the highest value of yield pressure (166 MPa) and thus the lowest compressibility among other mixtures. Furthermore, the addition of microcrystalline cellulose and α-lactose monohydrate has affected the crystallinity as well as the tableting properties of the co-crystals. After the addition of excipients, the tensile strength of compacts was about 2 times higher than any other mixture. Finally, urea/ 2-MB and caffeine/ malonic acid co-crystals were successfully synthesized through convection mixing and compaction. / Islamic University of Omdurman and the Ministry of Higher Education in Sudan

Surface energetics play a key role in the delivery of a dry powder inhaler formulation into the lungs, as there must be a sufficient balance of adhesive and cohesive forces to allow optimal lung delivery. In this study, measuring the surface energies of a set of single drug and carrier (budesonide or theophylline with either mannitol or lactose) with different levels of surfactant using Inverse Gas Chromatography, and comparing them to their lung deposition performance using a Next Generation Impactor established a relationship between the two. A 1:10 mixing ratio of budesonide with either carrier was found to have the highest FPF. Coating the carriers with 0.05% sodium lauryl sulphate resulted in a further increase in the FPF when using either budesonide or theophylline as the API, and the same results were seen when a sonocrystallised version of the API was substituted for the micronised form. The calculated IGC values then showed that the highest performing formulations had the lowest dispersive energy and total free surface energy. Furthermore, a trend was observed in the work of adhesion (Wa) and work of cohesion (Wc) for each set of formulations depending on which API was chosen, where for the less polar drug (budesonide) a higher Wa/Wc ratio was associated with the highest formulation performance, and for the more polar drug (theophylline) a smaller Wa/Wc ratio was associated with the highest formulation performance, enabling the estimation of lung performance for a set of single drug and carrier using their surface energy data. / Kuwait’s government and the Ministry of Health of Kuwait

Riboswitches have gained attention as tools for synthetic biology, since they enable researchers to reprogram cells to sense and respond to exogenous molecules. In vitro evolutionary approaches produced numerous RNA aptamers that bind such small ligands, but their conversion into functional riboswitches remains difficult. We previously developed a computational approach for the design of synthetic theophylline riboswitches based on secondary structure prediction. These riboswitches have been constructed to regulate ligand dependent transcription termination in Escherichia coli. Here, we test the usability of this design strategy by applying the approach to tetracycline and streptomycin aptamers. The resulting tetracycline riboswitches exhibit robust regulatory properties in vivo. Tandem fusions of these riboswitches with theophylline riboswitches represent logic gates responding to two different input signals. In contrast, the conversion of the streptomycin aptamer into functional riboswitches appears to be difficult. Investigations of the underlying aptamer secondary structure revealed differences between in silico prediction and structure probing. We conclude that only aptamers adopting the minimal free energy (MFE) structure are suitable targets for construction of synthetic riboswitches with design approaches based on equilibrium thermodynamics of RNA structures. Further improvements in the design strategy are required to implement aptamer structures not corresponding to the calculated MFE state.