Finally, the pharmacodynamic effects of propranolol powder formulation with different buffering were carried out in two healthy male subjects. The maximal reduction in heart rate was found at the saliva pH of 7.6, which corresponded to the pHmax of propranolol. A buffered propranolol sublingual tablet was then prepared to achieve the saliva pH around 7.6. The preliminary investigation confirmed that the sublingually administrated buffered propranolol tablet produced a faster and more pronounced heart rate reduction than the non-buffered commercial propranolol tablet. / Firstly, the use of the HO-1-u-1 cell culture for screening sublingual drug delivery was validated. The cells were seeded on cell culture inserts. The integrity of cell layers, inter-passage variation and directionality were assessed by measuring the resistance and the permeability of standard markers, beta-blockers and calcium channel blockers. The effect of pH, osmolarity and a permeation enhancer (GDC) were also studied. The results showed that HO-1-u-1 cells grown on inserts formed stratified and epithelial-like structure that preserved the typical histological feathers of the normal human sublingual epithelium. The maximal integrity was reached in 23 days. The Papp of beta-blockers and calcium channel blockers ranged from 2.89+/-0.17 x 10 -6 cm/s to 6.37+/-0.37 x 10-6 cm/s. The permeability of selected beta-blockers under different pH, osmolarity and GDC revealed that enhancing effects were significant for hydrophilic compounds but less for lipophilic compounds. / Secondly, fresh porcine sublingual mucosa was prepared and compared to the cell line model. Good correlations were obtained for both the Papp of beta-blockers and the enhancement ratios of pH and GDC between the two models. / The aims of the present study are (1) to develop and validate a human sublingual epithelial cell line model and (2) to demonstrate the application in sublingual development of cardiovascular drugs. / Thirdly, the steady-state flux (Jss) at various pH levels were measured. Results show that saturated propranolol solution at pH 7.0--7.6 resulted in a much higher Jss than the solution at other pHs. These data led to the development of theoretical equations for predicting the optimum pH (pHmax) for ionizable compounds. The calculation fitted well with the experimental data. / Wang Yanfeng. / Advisers: Moses S. S. Chow; Zhong Joan Zuo. / Source: Dissertation Abstracts International, Volume: 73-01, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (leaves 184-). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

El objetivo general que se ha planteado en este trabajo de tesis ha sido la obtención de nanopartículas magnéticas (NMPs) que puedan presentar aplicaciones biomédicas. El tipo de NPMs desarrolladas han sido, por una parte, magnetoliposomas, y, por otra, un ferrofluido formado por magnetita estabilizada con polietilenglicol (PEG). Como premisas de partida, se ha fijado que cualquier muestra obtenida de tener un tamaño inferior a 200 nm, estabilidad mínima de 24 horas, y un comportamiento propio de los ferrofluidos ante un campo magnético. Sobre aquellos productos que cumplían los citados requisitos se han ido introduciendo modificaciones hasta obtener un producto estable con las propiedades antes indicadas. Se estudiaron dos aplicaciones terapéuticas de las partículas sintetizadas: como sistemas adecuados para terapia hipertérmica, y como sistemas transportadores de fármacos dirigidos bajo la acción de un campo magnético. Los magnetoliposomas obtenidos encapsulaban o bien un ferrofluido aniónico comercial, o bien el ferrofluido obtenido con PEG en liposomas empleando el método de fase reversa seguida de extrusión. Estos liposomas presentaban un diámetro de partícula de unos 200 nm, eran superparamagnéticos, muy estables y con las tasas de encapsulación más elevadas que las obtenidas por otros métodos. Se ha obtenido un ferrofluido por co‐precipitación de sales férricas en presencia de PEG. El PEG no estaba modificado y su interacción con la magnetita es de tipo físico. Se han obtenido nanopartículas de magnetita con un tamaño medio de 12 nm. Se ha estudiado el efecto de hipertermia y termoablación inducida de estas NPMs en fantoms, materiales con propiedades dieléctricas y de permitividad semejantes a los tejidos reales sobre los que se pretende aplicar la terapia. Se comprobó el funcionamiento de los aplicadores de radiación, una guía de onda y una antena de microondas, así como, el uso de las NPMs como potenciadores y como agentes para focalizar la energía en la zona deseada. Se demostró, que utilizando en conjunto el aplicador con las NPMs es posible focalizar la energía sobre el tumor evitando el calentamiento del tejido sano circundante, lograr incrementos de temperatura en el rango terapéutico y controlar los incrementos de temperatura en el tejido. Se ha estudiado la biodistribución de los magnetoliposomas en ratones a los que se les había inducido inflamación. Se confirmó que las NPMs se acumulan principalmente en el foco inflamatorio sin la necesidad de dirigirlos mediante un campo magnético externo. En un segundo estudio se observó que, además, si se le aplica en la zona inflamatoria un campo magnético externo, la cantidad de NPMs aumenta en el exudado, y disminuye en sangre, hígado y bazo. Esto demuestra que los magnetoliposomas pueden ser utilizados como vehículo de transporte, para dirigir fármacos a zonas de interés terapéutico, con lo que podríamos reducir la dosis de fármaco administrada y aumentar la eficacia del tratamiento y prevenir los efectos secundarios. / To obtain magnetic nanoparticles (MNPs) for biomedical applications was the primary objective of this thesis. Two types of MNPs have been developed. On one hand, magnetoliposomes and secondly, a ferrofluid formed by magnetite stabilized with polyethylene glycol (PEG). As a starting premise, samples of 200 nm, 24 h minimum stability and proper behavior of ferrofluids to a magnetic field are set to be the starting premises of this research. Specific modifications have been introduced to products that fulfill these requirements in order to obtain a stable product with the properties mentioned above. Two therapeutic applications of synthesized particles were studied as suitable systems for hyperthermia therapy, and as targeted drug carrier systems under the action of a magnetic field. The obtained magnetoliposomes encapsulate a commercial anionic ferrofluid or the ferrofluid stabilized with PEG inside liposomes using the method of reverse phase followed by extrusion. These liposomes have a particle diameter of 200 nm, are superparamagnetic, very stable and encapsulation rates higher than those obtained by other methods. Using co‐precipitation method of ferric salts in the presence of PEG the ferrofluid was obtained. The PEG was not modified and its interaction with the magnetite is of physical type. MNPs we obtained with an average size of 12 nm. The effect of induced hyperthermia and thermal ablation of these NPMS in phantoms have been studied. Phantoms are materials with dielectric and permittivity properties tissues‐like in which the therapy is intended to be applied. We demonstrated the operation of the radiation applicator, a waveguide and a microwave antenna, and also the use of NPMS as enhancers and agents to focus the energy on the desired area. It was demonstrated the usage of applicator together with the NPMS is possible to focus the energy on the tumor while sparing the surrounding healthy tissue heating. Furthermore an enhanced of the temperature on the therapeutic range and the control of the increases of temperature in the tissue were obtained. We have studied the biodistribution of magnetoliposomas in mice that had been induced inflammation. NPMS was confirmed to accumulate mainly in the inflammatory focus directing without using an external magnetic field in the exudate. Moreover, in a second study it was observed that, if this external magnetic field was applied in the inflammatory area, the amount of NPMS increases in the exudate and decreases in blood, liver, and spleen. This demonstrate that magnetoliposomas can be used as transport vehicle for drug targeting to areas of therapeutic interest, and reduce the dose of drug administered and increases the efficiency of the treatment preventing side effects.