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Wilding, Ian Robert. "Some studies of oral sustained release of pellet systems." Thesis, University of Nottingham, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.319343.
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Mahbubani, Krishnaa Trishna Ashok. "Vehicles for the oral delivery of live bacteria." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608290.
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Aldosari, Basmah Nasser Abdullah. "Development and evaluation of self-nanoemulsifying drug delivery systems for oral delivery of indomethacin." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10044225/.
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In this study, indomethacin-loaded self-nanoemulsifying drug delivery systems (SNEDDS) were developed in liquid, solid and carrier-mediated formulations in order to improve the solubility of this model poorly water soluble drug. Liquid SNEDDS based on CapryolTM 90 (oil phase), Cremophor® RH 40 (surfactant) and Transcutol® HP (co-surfactant) were thermodynamically stable and produced clear nanoemulsions upon dilution. Optimized liquid formulations were transformed into solid SNEDDS by adsorption onto the inert carriers Syloid® XDP 3150, Neusilin® US2 and Florite® PS-200. Ratios of adsorbent: liquid SNEDDS of 1:1.5 and 1:2 resulted in solid SNEDDS formulations that exhibited fair to passable powder flow properties. Carrier-based solid SNEDDS formulations were developed using the solid self-emulsifying carriers Gelucire® 44/14 and Gelucire® 48/16 and prepared by hot melt extrusion. The absorbent-based solid SNEDDS maintained the self-nanoemulsification properties of the original liquid SNEDDS formulations, with solid state analysis suggesting that the drug had remained in a dissolved state within these formulations. Similarly, physical characterization of the carrier-based solid SNEDDS formulations indicated that the drug was molecularly dispersed within the system and that the self-nanoemulsifying properties of the carrier were unchanged. The only exception was those formulations prepared at the highest drug: carrier ratio (3: 10). For both absorbent-based and carrier-based solid SNEDDS, the in vitro dissolution efficiency was significantly higher than that obtained for the pure drug. However, incorporation of adsorbents into Gelucire®-based solid SNEDDS formulations resulted in reduced dissolution of the drug. Gelucire®48/16-based solid SNEDDS prepared at 50oC were more physically stable to storage at 30oC/75% RH for 6 months than formulations processed at 40oC, suggesting that complete melting of the carrier during manufacture is essential for production of physically stable formulations. Overall, a range of liquid, solid and carrier-based SNEDDS formulations were successfully developed and offer useful alternatives to improving the solubility of poorly water-soluble drugs.
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Low, Bee Koen. "Investigation of hydrophilic materials in time-delayed oral delivery systems." Thesis, University of Strathclyde, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288718.
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Al, Sukhun Rajaa Abed El-Kader. "Lipid drug delivery systems and their fate after oral administration." Thesis, University of Bath, 2002. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.665369.
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A novel class of lipid formulation was investigated comprising GRAS (generally regarded as safe) materials. The formulations were all ‘surfactant-free’ (S-F) formulations, and also referred to as ‘Type IV’ lipid formulations. These formulations were isotropic, transparent, thermodynamically stable at room temperature and typically composed of > 50 % of mixed mono-, di- and triglycerides, > 30 % medium chain fatty acids oil and < 20 % hydrophilic co-solvent. At equilibrium, S-F formulations enhanced the solvent capacity of corticosteroids (log P > 3) and hydroxy benzoate derivatives over type II SEDDS and type III SEDDS, but generally were not superior solvents to mixtures of mono-, di- and triglycerides (Imwitor 988® and or Capmul MCM®) alone, for lipophilic steroids (log P < 3). In general, type III SEDDS which were composed of high hydrophilic content (hydrophilic surfactant, HLB > 1 2 , and hydrophilic co-solvent), were also better solvents for most steroidal compounds and hydroxy benzoate derivatives than type II SEDDS and type I SEDDS formulations. Surfactant with HLB > 12 inhibited lipolysis of MCT and mixed glycerides when the concentration of surfactant exceeded 40 % w/w. Hydrophobic surfactants (HLB < 10) did not inhibit lipolysis. Thus, the digestibility of dispersions formed by selfemulsifying systems would be dependent on the surfactants used and the quantity of TG available for lipolysis. Co-solvents did not appear to influence lipolysis, once the formulations had dispersed. Phase separation of lipid formulations following their dispersion in simulated intestinal fluid was studied. The lipid formulation behaviour was dependent on monoglyceride content. When sufficient monoglyceride (> 60 %w/v) was present demulsification and phase separation was noticed and was found to be dependent on the presence of phospholipid. This resulted in sedimentation of the phase rich V monoglyceride and water. The presence of triglyceride stabilised the formation of mixed micelles, which remained in a finely dispersed state. This unexpected phase separation is likely to have a considerable effect on the fate of drug dissolved in SEDDS formulations. The high concentrations of monoglyceride may be disadvantageous and could possibly result in precipitation of drug.
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Mota, Joana [Verfasser]. "Matrix- and reservoir-type oral multiparticulate drug delivery systems / Joana Mota." Berlin : Freie Universität Berlin, 2010. http://d-nb.info/1024784770/34.
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Samaligy, Samar el [Verfasser]. "Floating Systems for Oral Controlled Release Drug Delivery / Samar El Samaligy." Berlin : Freie Universität Berlin, 2010. http://d-nb.info/1024784614/34.
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Arca, Hale Cigdem. "Cellulose Esters and Cellulose Ether Esters for Oral Drug Delivery Systems." Diss., Virginia Tech, 2016. http://hdl.handle.net/10919/82920.
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Amorphous solid dispersion (ASD) is a popular method to increase drug solubility and consequently poor drug bioavailability. Cellulose ω-carboxyesters were designed and synthesized specifically for ASD preparations in Edgar lab that can meet the ASD expectations such as high Tg, recrystallization prevention and pH-triggered release due to the free -COOH groups. Rifampicin (Rif), Ritonavir (Rit), Efavirenz (Efa), Etravirine (Etra) and Quercetin (Que) cellulose ester ASDs were investigated in order to increase drug solubility, prevent release at low pH and controlled release of the drug at small intestine pH that can improve drug bioavailability, decrease needed drug content and medication price to make it affordable in third world countries, and extent pill efficiency period to improve patient quality of life and adherence to the treatment schedule. The studies were compared with cellulose based commercial polymers to prove the impact of the investigation and potential for the application. Furthermore, the in vitro results obtained were further supported by in vivo studies to prove the significant increase in bioavailability and show the extended release.
The need of new cellulose derivatives for ASD applications extended the research area, the design and synthesis of a new class of polymers, alkyl cellulose ω-carboxyesters for ASD formulations investigated and the efficiency of the polymers were summarized to show that they have the anticipated properties. The polymers were synthesized by the reaction of commercial cellulose alkyl ethers with benzyl ester protected, monofunctional hydrocarbon chain acid chlorides, followed by removal of protecting group using palladium hydroxide catalyzed hydrogenolysis to form the alkyl cellulose wcarboxyalkanoate. Having been tested for ASD preparation, it was proven that the polymers were efficient in maintaining the drug in amorphous solid state, release the drug at neutral pH and prevent the recrystallization for hours, as predicted.Ph. D.
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Sankaranarayanan, Thampi Sajeesh. "Development of advanced drug delivery systems based on polymethacrylic acid nano/microparticles for oral insulin delivery." Paris 11, 2010. http://www.theses.fr/2010PA114805.
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L’étude a portée sur le développement de micro- et nanoparticules polymères destinées à l’administration orale d’insuline. Une méthode de polymérisation radicalaire a été optimisée pour formuler des micro et des nanoparticules à base d’un polymère formant des hydrogels, le poly(acide de méthacrylique). Les particules ont ensuite été modifiées par greffage de résidus cystéine pour introduire des fonctions thiol en vue de renforcer les propriétés de bioadhésion et de promoteur d’adsorption des systèmes obtenus. Les particules ont montré des propriétés intéressantes de chargement en insuline et la libération se fait selon un mode de libération pH sensible. En effet, alors que l’insuline est majoritairement retenue dans la forme pharmaceutique à pH acide correspondant à un milieu gastrique, elle est libérée à un pH neutre voire légèrement basique retrouvé au niveau de l’intestin. Les systèmes ont montré une bonne capacité à améliorer le passage de l’épithélium intestinal sur des monocouches de cellules Caco 2 et sur de l’intestin isolé monté en chambres de Ussing. Au final, ces systèmes ont permis d’induire in vivo une réduction de la glycémie chez des animaux diabétiques et après une administration orale. Les essais menés sur des insulines modifiées ont permis d’identifier une stratégie de modification intéressante basée sur l’association de l’hormone à une cyclodextrine. En revanche, nos résultats suggèrent que la PEGylation de l’insuline n’apporte aucun bénéficeThe work carried out in this thesis was aimed to develop polymer micro- and nanoparticles for the oral administration of insulin. A method of radical polymerization was optimized to design micro and nanoparticles with a hydrogel forming polymer, poly(methacrylic acid) (PMAA). The particles were further modified by the grafting of cystein residues in order to introduce thiol functions which are believed to reinforce mucoadhesive and permeation enhancing properties of the formulation. The particles showed interesting loading properties for insulin and the release of the hormone was found to be pH dependent. Although insulin was mainly retained by the hydrogel particle in releasing medium mimicking the gastric environment, the hormone was released in conditions found in the intestine. The formulated systems have shown to improve the absorption of insulin through the intestinal mucosa in in vitro models including Caco 2 cell monolayers and the Ussing chambers. The microparticles selected from the in vitro experiments for in vivo studies have shown a capacity to deliver active insulin through the oral route to diabetic rats producing a reduction of the glycemia. Tests performed with modified insulin have allowed to identify that among the two strategies followed, this consisting on the association of insulin with a cyclodextrin was the most promising while the one based on the formation of an insulin-PEG conjugate did not brought any benefice
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Swai, Hulda Paulo Shaidi. "Water sorption and drug release behaviour of polymeric systems based on heterocyclic/cyclic methacrylates." Thesis, Queen Mary, University of London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313482.
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Coombs, Gemma. "The design and characterisation of multiparticulate lipidic systems for oral drug delivery." Thesis, University of Strathclyde, 2013. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=19020.
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The aim of the current research was to develop a sustained release hydrophobic matrix drug delivery system utilising extrusion spheronisation. The initial formulation supplied was Sebomin® MR 100mg capsules, an oral modified release commercial product. A technological transfer was undertaken to reproduce the Sebomin® multiparticulate product utilising lab-scale extrusion/spheronisation equipment. On successful completion, modulation of various processing parameters and the effect on the resultant granule and pellet characteristics evaluated. The potential to develop a sustained release wax matrix formulation via the current technology was unsuccessful and led to the development of a hot-melt spray system. To characterise and validate the hot-melt spray system, OFAT and experimental design approaches were utilised. The process proved to be robust and reproducible in the production of sprayed wax granules. A stability study of the sprayed glyceryl monostearate (GMS) granules indicated the production of the unstable α-form of GMS, during storage the GMS reverted into the stable β-form. Incorporation of active pharmaceutical ingredients and additional excipients into the sprayed wax matrix system enabled in-vitro properties to be evaluated from both sprayed solid solutions and solid dispersions. Screening techniques including differential scanning calorimetry, FT-IR, hot-stage microscopy, X-ray powder diffraction, scanning electron microscopy and dissolution testing were successfully employed to identify changes to the physicochemical properties of materials that may impact product performance.
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Lockwood, Peter John. "The development and characterisation of directly-compressible oral controlled drug delivery systems." Thesis, University of Bath, 1990. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.760612.
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Chigwanda, Tapuwa Rosemary Jabulani. "The investigation of a hydrophobic matrix for oral controlled drug delivery systems." Thesis, University of Bath, 1995. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307118.
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Araya, Tanya, and Katie Coates. "Comparing the Absorption of Different Hormone Delivery Systems: A Meta-Analysis." The University of Arizona, 2006. http://hdl.handle.net/10150/624506.
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Class of 2006 AbstractObjectives: To create a conversion chart of non-oral estrogen replacement systems based on Cavg. Design: Meta-analysis. Methods: A literature search using two databases, drug manufacturer data, and the online FDA new drug application website was performed in May 2005. Of the original studies identified, those that were selected for analysis met the following inclusion criteria: 1) English in language 2) only included human subjects 3) reported the average blood concentration (Cavg) and 4) were not baseline adjusted. The Cavg data was entered into a spreadsheet and analyzed by an independent statistician. Results: Fifty studies were originally identified. Of these 50 studies, only 22 met inclusion criteria and were used to calculate the mean Cavg of different administration systems. The Cavgs were then used to create a comparison chart. Conclusions: Overall, there has been little research done that examines blood estradiol levels achieved through non-oral administration routes. The chart created from this meta-analysis is vital to health care providers because it allows a patient to be converted from one route to another while assuring the provider that the patient is receiving the same therapeutic benefit.
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Martí, Coma-Cros Elisabet. "Investigation of branched and linear polymers as oral delivery systems of antimalarial drugs." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/667687.
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Malaria is an infectious disease that affects nearly half of the population in 90 countries around the world. In 2017 it was estimated that there were 219 million cases and 435,000 deaths disproportionately distributed worldwide. Indeed, 92 % of malaria cases and 93 % of malaria deaths occur in Africa, while the remaining of the cases are distributed among South East-Asia, Eastern Mediterranean, Western Pacific, and the Americas. Vast global efforts and large economic investments have been made to reduce, control and eliminate malaria, resulting in a great reduction of the incidence in the last two decades. Nevertheless, malaria remains a global public health issue. Actually, malaria in humans is caused by an intracellular protist which has an extremely complicated live cycle that occurs within two hosts, the human and the Anopheles vector. There are five parasite species of the genus Plasmodium capable to infect humans P. ovale, P. malariae, P. knowlesi, P. vivax and P. falciparum, the latter being responsible for the majority of the morbidity and mortality of this disease. Malaria is a treatable disease, however antimalarial drugs must cross at least three sequential membranes (EPM, PVM and PPM) in order to enter the intracellular parasite and reach appropriate therapeutic concentrations; reason why they required drug delivery systems (DDSs). In fact, nano-DDSs have shown to have a positive effect on disease treatment providing solutions to solubility, pharmacokinetics, target selectivity, and/or protection against degradation, resulting in a drug half-life increased. The aim of this thesis was to characterize different polymeric nanocarrier, branched or dendrimeric (DHP-bMPA and HDLDBC-bGMPA) and linear polyamidoamines (PAAs) (AGMA1, ISA1, ISA23 and ARGO7), as oral drug delivery systems. Results obtained performing in vitro experiments demonstrated that PAAs and dendrimers have low unspecific toxicity, no hemolitic activity, specific pRBCs targeting and drug encapsulation capacity. Furthermore, PAAs displayed slow degradation, affinity to parasite proteins, which could explain the preferential binding to pRBCs, and intake by macrophages, indicating PAAs potential to treat other intracellular parasitic disease like Leishmaniasis. Additionally, dendrimers that form spontaneous micellar carrier, and bind to merozoites, showed an intake by HUVEC cells in different location, which could be further investigated to treat as well other disease. On the other hand, encapsulated drugs with the two types of polymers showed optimal in vivo capacity to inhibit Plasmodium growth after i.v or oral administration. Moreover, when PAA-FITC where given to female mosquitoes’ fluorescence was observed in the midgut and in the insect’s tissues. In conclusion, the date showed in this thesis work presented the branched and the linear polymers investigated as a versatile platform for the encapsulation of orally administrated antimalarial drugs, for the direct administration of antimalarial to mosquitoes, and as potential carriers for the treatment of other parasitic diseases.La malària és una malaltia infecciosa que afecta gairebé a la meitat de la població de 90 països d'arreu del món. El 2017 s'estima que va provocar 219 milions de casos i 435.000 morts, el 92% de casos i el 93% de morts es produïren a l'Àfrica. Els darrers anys s'han fet grans esforços globals i inversions econòmiques per reduir, controlar i eliminar la malària, cosa que ha comportat una gran reducció de la incidència en els últims 20 anys. No obstant això, aquesta malaltia continua sent un problema de salut pública global. En humans és causada per un protozou del gènere Plasmodium i concretament se’n coneixen cinc espècies diferents. Però la causant de més morbiditat i mortalitat és P. falciparum. La malaltia en si és tractable, però els fàrmacs antipalúdics han de creuar com a mínim tres barreres seqüencials per tal d'arribar al paràsit a una concentració suficientment elevada. Per això aquests principis actius requereixen sistemes d'administració de fàrmacs que han demostrat tenir efectes positius. L'objectiu d'aquesta tesi ha estat caracteritzar polímers ramificats (DHP-bMPA i HDLDBC-bGMPA) i lineals (AGMA1, ISA1, ISA23 i ARGO7) per l'administració oral d'antipalúdics. Els resultats obtinguts realitzant experiments in vitro i in vivo han demostrat que tots dos tipus de polímers tenen baixa toxicitat inespecífica, no tenen activitat hemolítica, tenen especificitat per pRBCs i bona capacitat d'encapsulació. Els PAAs han demostrat tenir una degradació lenta, afinitat per proteïnes del paràsit, i capacitat per entrar dins de macròfags, una propietat interessant per tractar altres malalties. A més a més els ramificats s'uneixen a merozoites i entren en macròfags. D'altra banda els medicaments encapsulats amb qualsevol dels dos tipus de polímers han mostrat una capacitat òptima in vivo per inhibir el creixement del Plasmodiuim després de l’administració i.v o oral. Per últim, PAAs-FITC administrats a mosquits femelles, s’han pogut observar a l'intestí i altres teixits. Per tant es pot concloure, que les dades recollides en aquesta tesi demostren que tant polímers ramificats com lineals són una plataforma versàtil per a l'encapsulació de medicaments antipalúdics per ser administrat via oral, per a l’administració directa a mosquits, i potencials nanocarriers pel tractament d’altres malalties parasitàries.
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Krenzlin, Stefanie [Verfasser]. "Challenging controlled drug delivery : matrix systems for oral and parenteral application / Stefanie Krenzlin." Berlin : Freie Universität Berlin, 2012. http://d-nb.info/1027816118/34.
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Challis, Deborah. "Physicochemical and biopharmaceutical studies of novel self-emulsifying systems for administration by the oral route (SEDDS)." Thesis, University of Bath, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.280871.
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Tuesca, Anthony D. Lowman Anthony M. "Synthesis, characterization, and application of polyethylene glycol modified insulin for oral delivery using complexation hydrogels /." Philadelphia, Pa. : Drexel University, 2008. http://hdl.handle.net/1860/2715.
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Eyries, Pascal. "A dynamic distributed-parameter modeling approach for performance monitoring of oral drug delivery systems." Link to electronic thesis, 2003. http://www.wpi.edu/Pubs/ETD/Available/etd-0501103-161142.
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Thesis (M.S.)--Worcester Polytechnic Institute.Keywords: mass balance approach; bioavailability; drug delivery; dynamic modeling; partial differential equations; sensitivity analysis; dynamic simulations. Includes bibliographical references (p. 62-67).
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Velghe, Carine. "Oral controlled drug delivery systems, optimization of release patterns and elucidation of release mechanisms." Thesis, Lille 2, 2013. http://www.theses.fr/2013LIL2S048/document.
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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. [...]
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Katragadda, Suresh Mitra Ashim K. "Design of amino acid prodrugs of acyclovir for improved bioavailability and therapeutic activity utility in treating ocular, oral and genital herpes infections /." Diss., UMK access, 2007.
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Thesis (Ph. D.)--School of Pharmacy and Dept. of Chemistry. University of Missouri--Kansas City, 2007."A dissertation in pharmaceutical sciences and chemistry." Advisor: Ashim K. Mitra. Typescript. Vita. Description based on contents viewed July 16, 2008; title from "catalog record" of the print edition. Includes bibliographical references (leaves 173-182). Online version of the print edition.
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Zhou, Yi. "Mechanisms of S-nitrosothiols intestinal permeability and NO store formation within vascular wall to improve NO oral delivery systems." Thesis, Université de Lorraine, 2019. http://www.theses.fr/2019LORR0101/document.
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Les S-nitrosothiols (RSNO) comme le S-nitrosoglutathion (GSNO) sont des donneurs de monoxyde d’azote (NO) prometteurs pour le traitement des maladies cardiovasculaires. Cependant, ce sont des candidats médicaments peu stables. Précédemment, des nanoparticules chargées en GSNO (GSNO-NP) ont été incluses dans une matrice d’alginate/chitosan. Les particules composites ainsi produites avaient une bonne encapsulation et une libération prolongée de GSNO. De plus, leur administration orale à des rats produisait un stock de NO au niveau de la paroi de l’aorte. Elles avaient cependant plusieurs limitations : préparation et caractérisation longues, manque de stabilité et de reproductibilité. Ce travail avait donc trois objectifs : (1) déterminer le mécanisme d’absorption intestinale des RSNO non formulés ; (2) évaluer la capacité des RSNO non formulés à créer un stock vasculaire de NO ; 3) optimiser la formulation de GSNO. Nous avons montré, dans un modèle in vitro de barrière intestinale, que la perméabilité intestinale de GSNO, S-nitroso-N-acétylcystéine (NACNO) et S-nitroso-N-acetylpénicillamine (SNAP) se fait par un mécanisme passif, principalement par voie transcellulaire (également paracellulaire pour SNAP), avec une perméabilité moyenne. Après avoir traversé la barrière intestinale, les RSNO atteindront les vaisseaux sanguins. Pour comparer leur capacité à former un stock vasculaire de NO dans des aortes (avec endothélium intact ou retiré), nous avons quantifié le stock, vérifié sa biodisponibilité pour la vasorelaxation et évalué son impact sur une vasoconstriction induite par la phénylephrine (PHE). L’incubation des aortes avec les RSNO augmente le stock basal de NO par un facteur trois à cinq. Ce stock est mobilisable pour induire la vasorelaxation et efficace pour diminuer la réactivité vasculaire à la PHE (NACNO>GSNO = SNAP), seulement dans les aortes dont l’endothélium a été retiré. Comme la perméabilité intestinale des RSNO est moyenne, l’intégration du GSNO dans une formulation appropriée est nécessaire. Vu l’impossibilité de résoudre les problèmes liés aux particules composites, le protocole de production des GSNO-NP a été modifié pour produire des microparticules (deux types selon l’état liquide ou solide de GSNO dans la phase interne de l’émulsion). Les deux types de microparticules avaient une libération de GSNO ralentie par rapport aux GSNO-NP. Les nano- comme les micro-particules ont pu être stabilisées par lyophilisation, et amélioraient la perméabilité intestinale de GSNO (jusqu’à une forte perméabilité avec les microparticules). Par conséquent, une administration orale de nano/microparticules chargées en GSNO/RSNO pourrait représenter une nouvelle approche thérapeutique pour les maladies cardiovasculairesS-nitrosothiols (RSNOs) such as S-nitrosoglutathione (GSNO) are promising nitric oxide (NO) donors for cardiovascular diseases treatment. However, they are poorly stable drug candidates. In previous studies, GSNO-loaded nanoparticles (GSNO-NP) were embedded into an alginate/chitosan matrix. Resulting nanocomposite particles showed high encapsulation and sustained release of GSNO, and led to the formation of a NO store in the wall of aorta after a single oral administration to rats. However, these nanocomposite particles have several limitations such as time-consuming preparation, lack of both stability and reproducibility. This thesis work aimed at: 1) Elucidate the mechanism of free RSNOs intestinal absorption; 2) Evaluate ability of free RSNOs to form a vascular NO store; 3) Optimize the GSNO formulation. In this study, we showed that the intestinal permeability (in vitro model of intestinal barrier) of GSNO, S-nitroso-N-acetylcysteine (NACNO) and S-nitroso-N-acetylpenicillamine (SNAP) was a passive diffusion, following the transcellular pathway (and also the paracellular way for SNAP) and belonging to the medium permeability class. After crossing the intestinal barrier, RSNOs will reach the vasculature. In order to compare the ability of free RSNOs to form a vascular store of NO either in endothelium-intact or endothelium-removed aortae, we quantified the store, verified its bioavailability for vasorelaxation and evaluated its impact on phenylephrine (PHE)-induced vasoconstriction. Incubation with RSNOs increased the basal NO store three to five times. This store is still bioavailable to induce vasorelaxation and efficient to induce vascular hyporeactivity to PHE (NACNO> GSNO = SNAP) only in endothelium-removed aortae. As intestinal permeability of RSNOs was in the medium class, the integration of GSNO into an appropriate delivery system is essential. Limitations of previously developed nanocomposites particles were impossible to bypass so the production process of GSNO-NP was modified (liquid or solid GSNO in the internal phase of the emulsion) to produce microparticles. Both kinds of microparticles exhibited a slower release of GSNO than GSNO-NP. Nano-and micro-particles were stable after lyophilization and presented an enhancement of GSNO intestinal permeability (up to high permeability class for microparticles). Thus, oral administration of GSNO/RSNO loaded nano/micro particles seems to be a promising avenue for the treatment of cardiovascular diseases
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Pestana, Kelly Chrystina [UNESP]. "Microemulsões biocompatíveis de anfotericina B para administração oral: estudo estrutural, liberação in vitro e farmacocinética pré-clínica." Universidade Estadual Paulista (UNESP), 2009. http://hdl.handle.net/11449/106310.
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pestana_kc_dr_arafcf.pdf: 1397611 bytes, checksum: 139f2c10e325976c56a9928f8e54e882 (MD5)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Anfotericina B (AmB) é o fármaco de escolha para o tratamento das infecções fúngicas invasivas, importante causa de morbidade e mortalidade em pacientes imunodeprimidos. A toxicidade da AmB na forma convencional tem estimulado o desenvolvimento de novas formulações para a administração do fármaco. Neste trabalho foram estudadas microemulsões óleo/água, contendo fosfatidilcolina de soja/tween 20 como agentes tensoativos, CaptexTM 200 como fase oleosa e tampão fosfato 50mM pH 7,2 como fase aquosa, com o objetivo de reduzir a toxicidade e aumentar a absorção oral da AmB. Os sistemas obtidos com diferentes proporções dos componentes foram descritos através de um diagrama de fase pseudo-ternário. As microestruturas foram caracterizadas por espalhamento dinâmico de luz (DLS), reologia, microscopia de luz polarizada e espalhamento de raios X a baixo ângulo (SAXS). Foi desenvolvido e validado um método por CLAE para a determinação de AmB em plasma para aplicação em estudo do perfil farmacocinético do fármaco veiculado na ME em ratos. A nefrotoxicidade da AmB foi avaliada pela determinação da creatinina plasmática dos ratos após administração oral da nova formulação desenvolvida (50 mg/kg), e comparada à administração da formulação convencional na mesma dose. Foi observado que o tamanho das gotículas das microemulsões aumenta quando a AmB é incorporada ao sistema. As amostras apresentaram comportamento Newtoniano e, dependendo da composição do sistema, antitixotropia foi observada. Também foi observado que a viscosidade aumenta com o aumento da fase oleosa assim como a formação de estruturas lamelares ordenadas que são desfavorecidas com a adição do fármaco. A incorporação do fármaco depende das proporções de fase oleosa e tensoativo. As interações da AmB...
Amphotericin B (AmB) is the drug of choice for therapy of invasive fungal infections, an important cause of morbidity and mortality among immunodeficient patients. The high toxicity of AmB in its conventional formulation have induced the development of innovative formulations for the drug administration. In this work, oil-in-water microemulsions containing soya phosphatidylcholine/Tween® 20 (1:1) as surfactant, captexTM 200 as oil phase, and phosphate buffer 50mM, pH 7.2 as aqueous phase were studied in order to reduce AmB toxicity and increase its oral absorption. Systems obtained with different proportions of the components were described by pseudoternary phase diagram. The microstructures of the system were characterized by dynamic light scattering (DLS), rheological behavior, polarized light microscopy and small angle X-ray scattering (SAXS). Was developed and validated a fast and selective HPLC method to determine AmB for application to study of pharmacokinetic profile of drug in rats. The nephrotoxicity of AmB was assessed by determining of rat plasma creatinine after oral administration of the novel formulation (50 mg/kg) and comparing with it a conventional formulation in the same dose. It was observed that the oil droplets size increase when AmB is incorporated into the system. The samples presented Newtonian behavior depending on the system composition. An anti-thixotropic behavior was found, as well, the viscosity increases withthe oil phase. The data showed the formation of ordered structures with lamellar arrangements in the drug unloaded systems and that order decrease with the drug incorporation. The AmB incorporation into the system was dependent on both the oil phase and surfactant. The interactions of AmB with the systems can control both the drug solubility and release... (Complete abstract click electronic access below)
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Pestana, Kelly Chrystina. "Microemulsões biocompatíveis de anfotericina B para administração oral : estudo estrutural, liberação in vitro e farmacocinética pré-clínica /." Araraquara : [s.n.], 2009. http://hdl.handle.net/11449/106310.
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Resumo: Anfotericina B (AmB) é o fármaco de escolha para o tratamento das infecções fúngicas invasivas, importante causa de morbidade e mortalidade em pacientes imunodeprimidos. A toxicidade da AmB na forma convencional tem estimulado o desenvolvimento de novas formulações para a administração do fármaco. Neste trabalho foram estudadas microemulsões óleo/água, contendo fosfatidilcolina de soja/tween 20 como agentes tensoativos, CaptexTM 200 como fase oleosa e tampão fosfato 50mM pH 7,2 como fase aquosa, com o objetivo de reduzir a toxicidade e aumentar a absorção oral da AmB. Os sistemas obtidos com diferentes proporções dos componentes foram descritos através de um diagrama de fase pseudo-ternário. As microestruturas foram caracterizadas por espalhamento dinâmico de luz (DLS), reologia, microscopia de luz polarizada e espalhamento de raios X a baixo ângulo (SAXS). Foi desenvolvido e validado um método por CLAE para a determinação de AmB em plasma para aplicação em estudo do perfil farmacocinético do fármaco veiculado na ME em ratos. A nefrotoxicidade da AmB foi avaliada pela determinação da creatinina plasmática dos ratos após administração oral da nova formulação desenvolvida (50 mg/kg), e comparada à administração da formulação convencional na mesma dose. Foi observado que o tamanho das gotículas das microemulsões aumenta quando a AmB é incorporada ao sistema. As amostras apresentaram comportamento Newtoniano e, dependendo da composição do sistema, antitixotropia foi observada. Também foi observado que a viscosidade aumenta com o aumento da fase oleosa assim como a formação de estruturas lamelares ordenadas que são desfavorecidas com a adição do fármaco. A incorporação do fármaco depende das proporções de fase oleosa e tensoativo. As interações da AmB... (Resumo completo, clicar acesso eletrônico abaixo)Abstract: Amphotericin B (AmB) is the drug of choice for therapy of invasive fungal infections, an important cause of morbidity and mortality among immunodeficient patients. The high toxicity of AmB in its conventional formulation have induced the development of innovative formulations for the drug administration. In this work, oil-in-water microemulsions containing soya phosphatidylcholine/Tween® 20 (1:1) as surfactant, captexTM 200 as oil phase, and phosphate buffer 50mM, pH 7.2 as aqueous phase were studied in order to reduce AmB toxicity and increase its oral absorption. Systems obtained with different proportions of the components were described by pseudoternary phase diagram. The microstructures of the system were characterized by dynamic light scattering (DLS), rheological behavior, polarized light microscopy and small angle X-ray scattering (SAXS). Was developed and validated a fast and selective HPLC method to determine AmB for application to study of pharmacokinetic profile of drug in rats. The nephrotoxicity of AmB was assessed by determining of rat plasma creatinine after oral administration of the novel formulation (50 mg/kg) and comparing with it a conventional formulation in the same dose. It was observed that the oil droplets size increase when AmB is incorporated into the system. The samples presented Newtonian behavior depending on the system composition. An anti-thixotropic behavior was found, as well, the viscosity increases withthe oil phase. The data showed the formation of ordered structures with lamellar arrangements in the drug unloaded systems and that order decrease with the drug incorporation. The AmB incorporation into the system was dependent on both the oil phase and surfactant. The interactions of AmB with the systems can control both the drug solubility and release... (Complete abstract click electronic access below)
Orientador: Anselmo Gomes de Oliveira
Coorientador: Rosangela Gonçalves Peccinini
Banca: Maria Palmira Daflon Gremião
Banca: Marco Vinícius Chaud
Banca: Newton Andreo Filho
Banca: Raul Cesar Evangelista
Doutor
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Eduardo, Da Silva Acarilia. "Nanotechnological delivery systems for the oral administration of active molecules : Polymeric microparticles and microemulsions applied to anti-inflammatory and anti-infectious drugs." Phd thesis, Université Paris Sud - Paris XI, 2013. http://tel.archives-ouvertes.fr/tel-00856598.
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This thesis was devoted to the development of innovative oral delivery systems for two different molecules. In the first part, microparticles (MPs) based on xylan and Eudragit® S-100 were produced and used to encapsulate 5-aminosalicylic acid for colon delivery. Xylan was extracted from corn cobs and characterized in terms of its physicochemical, rheological and toxicological properties. The polymeric MPs were prepared by interfacial cross-linking polymerization and spray-drying and characterized for their morphology, mean size and distribution, thermal stability, crystallinity, entrapment efficiency and in vitro drug release. MPs with suitable physical characteristics and satisfactory yields were prepared by both methods, although the spray-dried systems showed higher thermal stability. In general, spray-dried MPs would be preferable systems due to their thermal stability and absence of toxic agents used in their preparation. However, drug loading and release need to be optimized. In the second part of this thesis, oil-in-water microemulsions (O/W MEs) based on medium-chain triglycerides were formulated as drug carriers and solubility enhancers for amphotericin B (AmB). Phase diagrams were constructed using surfactant blends with hydrophilic-lipophilic balance values between 9.7 and 14.4. The drug-free and drug-loaded MEs presented spherical non-aggregated droplets around 80 and 120 nm, respectively, and a low polydispersity index. The incorporation of AmB was high and depended on the volume fraction of the disperse phase. These MEs did not reduce the viability of J774.A1 macrophage-like cells for concentrations up to 25 µg/mL of AmB. Therefore, O/W MEs based on propylene glycol esters of caprylic acid may be considered as suitable delivery systems for AmB.
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Silva, Acarilia Eduardo da. "Nanotechnological delivery systems for the oral administration of active molecules: Polymeric microparticles and microemulsions applied to anti-inflammatory and anti-infectious drugs." Universidade Federal do Rio Grande do Norte, 2013. http://repositorio.ufrn.br:8080/jspui/handle/123456789/13309.
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Previous issue date: 2013-04-05Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico
This thesis was devoted to the development of innovative oral delivery systems for two different molecules. In the first part, microparticles (MPs) based on xylan and Eudragit? S- 100 were produced and used to encapsulate 5-aminosalicylic acid for colon delivery. Xylan was extracted from corn cobs and characterized in terms of its physicochemical, rheological and toxicological properties. The polymeric MPs were prepared by interfacial cross-linking polymerization and spray-drying and characterized for their morphology, mean size and distribution, thermal stability, crystallinity, entrapment efficiency and in vitro drug release. MPs with suitable physical characteristics and satisfactory yields were prepared by both methods, although the spray-dried systems showed higher thermal stability. In general, spraydried MPs would be preferable systems due to their thermal stability and absence of toxic agents used in their preparation. However, drug loading and release need to be optimized. In the second part of this thesis, oil-in-water microemulsions (O/W MEs) based on mediumchain triglycerides were formulated as drug carriers and solubility enhancers for amphotericin B (AmB). Phase diagrams were constructed using surfactant blends with hydrophiliclipophilic balance values between 9.7 and 14.4. The drug-free and drug-loaded MEs presented spherical non-aggregated droplets around 80 and 120 nm, respectively, and a low polydispersity index. The incorporation of AmB was high and depended on the volume fraction of the disperse phase. These MEs did not reduce the viability of J774.A1 macrophage-like cells for concentrations up to 25 μg/mL of AmB. Therefore, O/W MEs based on propylene glycol esters of caprylic acid may be considered as suitable delivery systems for AmB
Esta tese teve como objetivo o desenvolvimento de novos sistemas de libera??o para duas mol?culas distintas. Na primeira parte, micropart?culas ? base de xilana e Eudragit? S-100 foram produzidas para encapsular ?cido 5-aminosalic?lico visando ? libera??o c?lonespec?fica. A xilana foi extra?da de sabugos de milho e caracterizada quanto ?s suas propriedades f?sico-qu?micas, reol?gicas e toxicol?gicas. Em seguida, dois m?todos de microencapsula??o foram utilizados: reticula??o interfacial polim?rica e secagem por aspers?o. Os sistemas produzidos foram caracterizados quanto ? morfologia, tamanho m?dio e distribui??o, estabilidade t?rmica, cristalinidade, taxa de encapsula??o e libera??o do f?rmaco in vitro. Foram obtidas micropart?culas com adequadas caracter?sticas f?sicas e rendimentos satisfat?rios atrav?s dos dois m?todos, embora os sistemas aspergidos tenham apresentado maior estabilidade t?rmica e sejam considerados mais interessantes devido a sua maior estabilidade t?rmica e aus?ncia de agentes t?xicos. No entanto, ajustes precisam ser feitos para melhorar a encapsula??o e libera??o do f?rmaco. Na segunda parte, microemuls?es do tipo ?leo em ?gua (MEs O/A) com base em triglicer?deos de cadeia m?dia (MCT) foram produzidas visando ao carreamento de anfotericina B (AmB) e aumento da sua solubilidade. Foram obtidas MEs O/A sem e com AmB com got?culas em torno de 80 e 120 nm, respectivamente, e ?ndices de polidispers?o de 0,25 e 0,31, respectivamente. A taxa de incorpora??o da AmB foi alta e dependente do volume da fase dispersa. A viabilidade celular n?o foi afetada at? 25 μg/mL da AmB. Portanto, MEs O/A a partir de MCT podem ser promissores sistemas de libera??o para AmB
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Salim, Nesreen. "Intra-oral delivery system for antifungal release." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/intraoral-delivery-system-for-antifungal-release(3c5e071a-7770-4cc6-aaea-5aa9ac71706a).html.
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Background: The placement of removable dental prostheses produces significant changes in the oral environment that may lead to adverse effects on the integrity of the oral tissues. Denture-induced candidosis, caused by candidal infection of the palatal mucosa, is the most frequent complication (40 %) in removable denture wearers. It predominantly affects immunosuppressed and medically compromised patients. In these high-risk patients the oral cavity may provide a source for Candida causing systemic infection. Oral candidosis has become a significant challenge in patients with persisting risk factors and a recurrent need for antifungal treatment. In addition, denture-induced candidosis is a mixed biofilm infection which provides multiple challenges for its management. Moreover, the persistent fungal colonisation on the fitting surfaces of denture often leads to cross infection and recurrence of mucosal lesions. These considerations highlight the clear need for new effective antifungal treatment modalities.Aims: The aims of this project were to establish a polymeric delivery device based on denture base lining polymer, poly (ethyl methacrylate) and tetrahydrofurfuryl methacrylate (PEM/THFM), for sustained delivery of antifungal agents [chlorhexidine (CHX) and fluconazole (FLU)], for the use in the treatment of denture-induced candidosis and to test the serviceability of the lining under investigation.Methods: A broth microdilution method was used to assess the spectrum of activity of the antifungal agents (CHX powder and FLU powder in two formulations pure and from capsules) against wide range of Candida species. Bioassay method and spectrophotometry were used to evaluate the efficiency of the PEM/THFM denture liner to release the impregnated antifungal agents and to quantify the released concentrations. Bioassay, time-kill studies and biofilm assays were used to verify the antifungal activity of the released antifungal agents. Shear bond test, water absorption, colorimetery and Fourier Transform Infrared Spectroscopy were used to test clinically important physical and mechanical properties for the impregnated liner.Results: It was found that CHX has broad-spectrum antifungal activity also among Candida species highly resistant to FLU. Both CHX and FLU became readily leached from PEM/THFM polymer up to 4 weeks in microbiologically effective concentrations. CHX demonstrated superior antifungal efficacy against planktonic and biofilm lifestyle of Candida compared to FLU. Findings show that the impregnation with antifungal agents has affected all tested properties (shear bond strength, water absorption, degree of conversion and colour stability) but these changes are comparable to other long-term lining materials and are within acceptable ranges.Conclusions: These findings indicate the feasibility of introducing an efficient treatment modality for candidal infections, especially denture-induced candidosis. A polymeric system containing CHX or FLU could assume a very promising treatment option as the drug is effective and directed to the site of pathology. Moreover, the distinct efficacy of CHX against C. albicans biofilms is a promising outcome to overcome the side effects of conventional antifungal agents and their reduced efficacy against biofilm formation.
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Tyrer, Peter Charles, and n/a. "Targeting M-cells for oral vaccine delivery." University of Canberra. Health Sciences, 2004. http://erl.canberra.edu.au./public/adt-AUC20060427.122012.
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An in vitro model of the follicle-associated epithelia that overlie the Peyer's patches of the
small intestine was developed and validated to examine the mechanisms of mucosal antigen
sampling. This model displays many phenotypic and physiological characteristics of M cells
including apical expression of [alpha]5[beta]l integrin and enhanced energy dependent participate
transport. CD4+ T-cells were shown to be an important influence on the development of Mlike
cells.
The model was used to examine the M cell mediated uptake of several putative whole-cell
killed bacterial vaccines. Greater numbers of non-typeable Haemophilus influenzae NTHi
289, NTHi 2019, Escherichia coli 075 HMN and Streptococcus pneumoniae were
transported by model M cells compared to control Caco-2 enterocyte-like cells. Studies in
isolated murine intestine segments confirmed the selective uptake of NTHi 289 and
Escherichia coli demonstrating that intestinal mucosal sampling of these antigens is
performed by M cells. Pseudomonas aeruginosa was not absorbed as whole cell bacteria but
as soluble antigen, as indicated by the presence of bacterial DNA in the cytoplasm of
epithelial cells. These results suggest that bacteria such as NTHi and E. coli are sampled by
the mucosal immune system in a different manner to that of bacteria such as Pseudomonas.
A number of potential cell surface receptors were investigated to identify which molecules
are responsible for intestinal uptake whole-cell killed bacteria. Immunofluorescence studies
detected the presence of toll-like receptor-2, toll-like receptor-4, PAF-R and [alpha]5[beta]l integrin
on in vitro M-like cell cultures. Examinations of murine intestine confirmed the presence of
TLR-4 and PAF-R. TLR-4 was found in small quantities and on M cells. In contrast to the M
cell model, TLR-2 expression in the murine intestine was sparse.
Receptor inhibition experiments provided evidence for the involvement of TLR-4, PAF-R
and [alpha]5[beta]l integrin in M cell uptake of killed bacteria both in vitro and in vivo.
This thesis has contributed valuable information regarding the mechanisms of uptake of
whole-cell killed bacteria by the intestinal mucosal immune system. For the first time, M cell
sampling of whole-cell killed bacteria has been demonstrated. Furthermore, the receptors
involved in these processes have been identified. This information will be of great use in the
development and optimisation of new oral vaccines.
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Goettsche, Thorsten [Verfasser], Roland [Akademischer Betreuer] Zengerle, and Gerald A. [Akademischer Betreuer] Urban. "IntelliDrug - controlled, oral drug delivery system as tooth implant." Freiburg : Universität, 2016. http://d-nb.info/1128574195/34.
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Yeh, Ming-Kung. "Biodegradable microparticles as delivery system for proteins and peptides." Thesis, University of Nottingham, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.319677.
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Al-Shamkhani, Aymen. "Evaluation of alginates of soluble drug delivery system for oral and systematic use." Thesis, Keele University, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.333515.
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Cassidy, Kim Julie. "Conversations between strangers : observable oral participation in the service delivery system." Thesis, Manchester Metropolitan University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392829.
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Flinn, Nicholas Sean. "A lipidic amino acid based system for peptide delivery and enhancing peptide immunogenicity." Thesis, University College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244682.
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Roberts, Mark J. J. "The production and characterization of a model microparticulate oral antigen delivery system." Thesis, University of Nottingham, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.291890.
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Cary, Jewel Maria. "Development of a Nanoparticle Vaccine Delivery System with Polymeric Oral Adjuvants for Poultry." Diss., Virginia Tech, 2019. http://hdl.handle.net/10919/102504.
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Development of new vaccination technology has been hindered by a lack of new adjuvants to enable development of protective immunity using different vaccine delivery methods. A vaccine delivery system using oral adjuvants would be applicable across species for both individual and mass vaccination in both the medical and veterinary fields. We sought to create an oral nanoparticle (NP) vaccine delivery system that is easy to produce and uses polymers as oral adjuvants with killed virus. Our hypothesis was gelatin and chitosan would enhance viral uptake and stimulate immune cells to produce protective immunity. This would allow the safer killed form of each virus to be used in place of modified live (MLV) viruses and avoid undesirable side effects like immunosuppression. The research objectives were to
1. Fabricate and characterize gelatin NPs encapsulating inert materials of similar size and shape to the viruses of interest for fabrication proof-of-concept
2. Modify the NP delivery system to minimize immune cell cytoxicity for the vaccine delivery application
3. Fabricate and characterize FPV and HEV viral nanoparticles' stability, cellular uptake/infectivity, and released viruses' ability to replicate
4. Compare the abilities of the killed HEV nanovaccine, killed HEV with loose gelatin and chitosan polymers (no nanoparticle), and a live HEV commercial vaccine to induce textit{in vivo} seroconversion, protective immunity, and side effects during clinical and challenge studies in turkeys
We proved our hypothesis to be correct in addition to demonstrating matching the encapsulation material size to empty NP size leads to preferred encapsulated NP formulation parameters, chitosan stabilizes the NP formulation bypassing the need for cytotoxic crosslinkers, and paraformaldehyde is able to kill virus prior to vaccine formulation while still preserving virus morphology sufficiently for immune cell recognition. This development constitutes one of the first novel adjuvants discoveries in 70 years and opens the door for conversion of injectable vaccines to oral delivery across species.Doctor of Philosophy
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Menina, Sara [Verfasser]. "Eap-functionalized liposomes as a bioinspired delivery system for oral delivery of colistin to treat intracellular Salmonella infection / Sara Menina." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2020. http://d-nb.info/1232726192/34.
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Mittal, Girish. "Biodegradable nanoparticles as a potential oral delivery system for oestradiol : pharmacokinetic and pharmacodynamic evaluations." Thesis, University of Strathclyde, 2010. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=12802.
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Lee, Wang Wang. "Factors affecting drug release and absorption from a novel oral delayed release drug delivery system." Thesis, Durham University, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269886.
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Pettit, Wendy Marie. "Towards the development of a multicomponent, nanoscale oral vaccine delivery system targeting infectious bursal disease (IBD)." Thesis, University of Greenwich, 2013. http://gala.gre.ac.uk/11376/.
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As the global population increases, estimated to reach 9 billion by the year 2050, global food security becomes a priority. A prominent disease implicated in financial loss to the poultry industry, on a global scale, is infectious bursal disease virus (IBDV). Vaccination against IBDV is sub-optimal and difficult to deliver. Therefore it has been highlighted as a key area for the development of an oral vaccine. A highly conserved capsid protein from IBDV (VP2) was identified, and sub-cloned into a bacterial expression cassette. This protein was fused to a potential carrier protein (cholera toxin B chain), previously shown to mediate the exit from the gut lumen into the lamina propria. However, to allow this antigen to reach the mucosal associated lymphoid tissue, the protein antigen must remain in its native conformation through the stomach. This work developed a delivery system to meet this end. By encapsulation within a fatty acid coated, protein adsorbed-solid core drug delivery system (SCDDS), it was shown that a model protein antigen (GST-GFP) could be protected from low pH (i.e. pH 2.0) and proteases. Protease protection was demonstrated against the exposure of myristic acid coated, GST-GFP adsorbed silica, to both protease K (100 μU, 1hour (100% protection)) as well as a simulated in vitro stomach environment (pepsin (0.2 mg) (100% protection)). Having demonstrated protection from proteases at pH 2.0 and pH7.4, it was then shown that GST-GFP could be released from the myristic acid coated silica at pH 8.8 (consistent with the small intestine). As much as ~15% (15 μg) (w/w) GST-GFP was released from the aforementioned system. The evidence supporting this conclusion was drawn from molar ellipticity calculations that showed the proportion of helical structure in relation to regions of beta sheet remained constant, pre-adsorption and post-release (16.9% α-helix, 20.8% β-sheet, 43.3% random coil). Finally, this work has shown that if a recombinant antigen was fused to cholera toxin B chain (but not shiga toxin B chain), it was capable of mediating transcytotic passage across, differentiated, polarised Caco-2 cells (1/1000th input (10 ng)). In conclusion and based upon the evidence provided above, this system warrants further optimisation and investigation to serve as an oral vaccine delivery system to treat IBDV.
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Almajdoub, Somaya Saleh. "Polymer Coating of an Optimized Nano Lipid Carrier System of Harpagophytum Procumbens Extract for Oral Delivery." University of the Western Cape, 2017. http://hdl.handle.net/11394/5893.
Full textAbstract:
Magister Pharmaceuticae - MpharmHarpagophytum procumbens is a traditional medicinal plant widely used in South African traditional healthcare to treat a range of ailments like degenerative rheumatoid arthritis, osteoarthritis, tendonitis, kidney inflammation, heart disease, dyspepsia and loss of appetite. Analgesic and anti-inflammatory effects of Harpagophytum procumbens has been reported to decrease due to stomach acidity. In addition, dried plant extract is water soluble and has poor lipid solubility severely limiting its ability to pass across lipid-rich biological membranes. To overcome this, plant extract was incorporated into a nano lipid alginate coated bead. Harpagophytum procumbens freeze dried aqueous extract was prepared and the active principle harpagoside was identified by mass spectrometry (MS). A simple, linear, accurate and precise UHPLC method was developed for quantitative determination of the bioactive harpagoside. Harpagophytum procumbens was encapsulated in lipid vesicles (liposomes and phytosomes) by using a dry film hydration technique and characterized for particle size, polydispersity index and encapsulation efficiency.
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Thay, Bernard. "Vesicle-mediated and free soluble delivery of bacterial effector proteins by oral and systemic pathogens." Doctoral thesis, Umeå universitet, Institutionen för odontologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-82782.
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Periodontitis, the primary cause of tooth-loss worldwide, is a bacterially induced chronic inflammatory disease of the periodontium. It is associated with systemic conditions such as cardiovascular disease (CVD). However, pathogenic mechanisms of periodontitis-associated bacteria that may contribute to the CVD association are unclear. The aim of this doctoral thesis project was to characterize bacterial mechanisms that can originate from the periodontal pocket and expose the host to multiple effector proteins, thereby potentially contributing to periodontal tissue degradation and systemic stimulation. As our main model, we have used Aggregatibacter actinomycetemcomitans, a Gram-negative species associated with aggressive forms of periodontitis, and with non-oral infections, such as endocarditis. Since Gram-positive species might be more common in periodontitis than previously believed, we have also investigated mechanisms of the multipotent bacterium, Staphylococcus aureus. Using an ex vivo insert model we showed that free-soluble surface material, released during growth by A. actinomycetemcomitans independently of outer membrane vesicles (OMVs), enhanced the expression of several proinflammatory cytokines in human whole blood. A clear LPS-independent effect suggested the involvement of effector proteins in this cytokine stimulation. This was supported by MALDI-TOF-MS and immunoblotting, which confirmed the release of GroEL and peptidoglycan-associated lipoprotein (PAL), in free-soluble form. We next demonstrated that A. actinomycetemcomitans OMVs could deliver multiple proteins including biologically active cytolethal distending toxin (CDT), a major virulence factor, into human gingival fibroblasts and HeLa cells. Using confocal microscopy, the active toxin unit, CdtB, was localized inside the nucleus of the intoxicated cells, whereas OmpA and proteins detected using an antibody specific to whole A. actinomycetemcomitans serotype a cells had a perinuclear distribution. By using a fluorescent probe, B-R18, it was shown that the OMVs fused with lipid rafts in the plasma membrane. These findings suggest that OMVs can deliver biologically active virulence factors such as CDT into susceptible cells of the periodontium. Using A. actinomycetemcomitans vesicles labeled with the lipophilic dye, PKH26, it was shown that the OMVs can be internalized into the perinuclear region of human cells in a cholesterol-dependent manner. Co-localization analysis supported that the internalized OMVs carried A. actinomycetemcomitans antigens. Inhibition assays suggested that although OMV internalization appeared to have a major role in effector protein delivery, additional interactions such as vesicle membrane fusion may also contribute. The OMVs strongly induced activation of the cytosolic pathogen recognition receptors NOD1 and NOD2 in HEK293T-cells, consistent with a role in triggering innate immunity by carrying PAMPs such as peptidoglycan into host cells. Membrane vesicles (MVs) from S. aureus were found to carry biologically active alpha-toxin, a key virulence factor, which was delivered to host cells and required for full cytotoxicity of the vesicles. Confocal microscopy analysis revealed that these MVs, similar to A. actinomycetemcomitans OMVs, interacted with HeLa cells via membrane fusion. Thus, as S. aureus is frequently found in individuals with aggressive periodontitis, MV production could have potential to contribute to the severity of tissue destruction.
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Rayasam, Revanth. "Oral delivery of insulin for diabetes therapy : the design, fabrication and characterisation of a modified-chitosan based nanoparticle system." Thesis, Kingston University, 2017. http://eprints.kingston.ac.uk/41955/.
Full textAbstract:
A number of innovative techniques were developed for the extra-vascular delivery of insulin, of which oral delivery of insulin being one of the most active fields of study in pharmaceutics. Interest in this domain is due to two factors: the therapeutic potential of the approach and lack of delivery systems which demonstrate promising results for clinical implementation. Oral delivery of insulin is of a particular challenge due to highly evolved and complex barriers presented by the gastrointestinal tract (GIT). Long-term s.c. injections are invasive and are associated with major drawbacks such as pain, weight gain, hypoglycaemia, hyperinsulinemia, leading to low patient compliance and adherence. The present work aims to develop novel insulin-loaded chitosan (CS) and pegylated chitosan (CS-O-mPEG) based nanoparticles (NPs) and investigate them for potential colonic delivery. PEG-Chitosan was chemically conjugated using low molecular weight chitosan and mPEG-2000. Insulin loaded pegylated chitosan (CS-O-mPEG) NPs were prepared via the iontropic gelation technique by cross-linking with tripolyphosphate (TPP). The characteristics of the NPs i.e. particle morphology, particle size and zeta potential was evaluated. The effect of pH and the polymer:TPP wieght ratios on NP characteristics was also evaluated. An HPLC analytical method to quantify insulin was developed and validated. In vitro release and entrapment studies of the nanoparticles were conducted using the Franz diffusion cells. Prepared nanoparticle formulations were assessed for biocompatibility using the MTT (Tetrazolim dye) assay and permeability studies on the Caco-2 and MDCK monolayers. Successful CS-O-mPEG conjugation was confirmed by FTIR and 1H NMR spectroscopy. SEM revealed the spherical nature of CS and CS-O-mPEG NPs. A mean diameter ranging from 50 - 250 nm was recorded for the NPs. Characterisation of NPs for zeta potential was carried out for both the CS and CS-O-mPEG formulations. Particle size measurements for the NPs revealed size ranges between 110-250 nm, in accordance to the hydradynamic diameter measured by DLS. RP- HPLC analytical method was developed and validated according to ICH guidelines to quantify Insulin. The data showed presence of well-defined single insulin peak, being successfully recovered at retention time between 7.5 - 9 minutes. CS-O-mPEG NPs demonstrated maximum release in simulated intestinal fluids (SIF). There was some encouraging data obtained in regard to the biocompatibility studies for the prepared Insulin loaded NP formulations using MTT assay. Permeability studies were also conducted for the prepared NP formulations on Caco-2 and MDCK monolayers, revealing better permeation of insulin through the CS-O-mPEG NPs. Insulin-loaded NPs of CS and CS-O-mPEG were successfully formulated. CS-O-mPEG NPs demonstrated superior in vitro characteristics over the conventional CS NPs in terms of aqueous solubility, particle size, entrapment efficiency and drug release profile, In addition, permeation studies revealed that CS-O-mPEG NPs enabled a significantly higher insulin transfer across Caco-2 and MDCK cell monolayer models compared to the CS NPs making the former a promising candidate for oral delivery of insulin.
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Nguyen, Thi Trinh Lan. "Extrusion- spheronization of pharmaceutical products : system for the delivery of active ingredients which are poorly soluble by oral route." Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAF047/document.
Full textAbstract:
L'amélioration de la dissolution des médicaments peu solubles présente de nombreux défis.Dans cette thèse, un procédé d'extrusion-sphéronisation a été étudié en profondeur pour améliorer la dissolubilité du médicament avec une formulation de nano-émulsion. Le but du travail de thèse est de décrire les propriétés et les procédés de fabrication de minigranules permettant d'augmenter la solubilité des principes actifs peu solubles dans l'eau et donc d‘améliorer leur biodisponibilité lors de l'administration par voie orale, pour deux modèles de molécules différentes qui sont l‘acide folique (vitamine peu soluble dans l'eau) et le kétoprofène (anti-inflammatoire non stéroïdien qui présente une solubilité limitée dans les fluides gastriques à cause de son pKa (classe II dans le système de classification biopharmaceutique – BCS, ayant une action anti-inflammatoire, antalgique et antipyrétique). Cette étude décrit la préparation par extrusion-sphéronisation, caractérisation et étude de dissolution in vitro d'acide folique et de pastilles de kétoprofène revêtues de Acryl-EZE®, Advantia® Performance dans un minicoatère à lit fluidisé. Les résultats des essais ont montré la faisabilité de la préparation de pastilles enrobées entériques contenant un AINS et que, en revêtant le système multiparticulaire avec Acryl-EZE® 93A92545 et Advantia® Performance190024HA49 à un gain pondéral de 17,5%, 12,0%, respectivement, du médicament à partir des pastilles peuvent être obtenus. Les résultats des essais de dissolution ont indiqué que dans un milieu acide, le revêtement de film a entraîné un retard dans la libération du médicament, alors qu'aucun retard n'a été observé dans un milieu tampon à pH 6,8Improvement in dissolution of poorly soluble drugs has many challenges.In this thesis, an extrusion-spheronization process was thoroughly studied forimproving dissolubility of drug with nano-emulsion formulation.The aim of the thesis work is to describe the properties and manufacturing processes ofpellets to increase the solubility of poorly soluble active ingredients in water and thus improvetheir bioavailability when administered orally: folic acid (water-insoluble vitamin) andketoprofen (Non-steroidal anti-inflammatory, having anti-inflammatory, analgesic andantipyretic action, class II in the Biopharmaceutical Classification System).This study describes the preparation by extrusion-spheronization, characterisation andin vitro dissolution study of folic acid and ketoprofen pellets. Ketoprofen pellets coated withAcryl-EZE®, Advantia® Performance in a fluid-bed minicoater. The results of the tests showedthe feasibility of the preparation of enteric-coated pellets containing a NSAID and that bycoating the multiparticulate system with either 17.5% Acryl-EZE® 93A92545 or with 12%Advantia® Performance 190024HA49 weight gain, an enteric release of the drug from thepellets can be obtained. The results of dissolution testing indicated that in acidic media, entericfilm coating resulted in a delay in the release of the drug, while no delay was observed in pH6.8 buffer media
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Liu, Quan. "Development of a novel gastro-retentive delivery system using alfuzosin HCl as a model drug." Diss., Temple University Libraries, 2010. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/80170.
Full textAbstract:
Pharmaceutics;Ph.D.
The objectives of this project encompass the design and development of a drug delivery system to continuously deliver therapeutic agents from the stomach to the proximal region of the intestine. The delivery system designed would have sufficient gastric residence time together with near zero-order release kinetics. The physicochemical properties pertaining to the formulation development of the model drug (alfuzosin HCl) were evaluated. Excipients were selected based on the studies of their physicochemical properties and compatibility with the active ingredient. Gastro-retentive dosage forms have been the topic of interest in recent years as a practical approach in drug deliveries to the upper GI tract or for release prolongation and absorption. These dosage forms are particularly suitable for drugs that have local effects on the gastric mucosa in the stomach. Other candidates include drugs that are likely to be absorbed in the upper small intestine, or drugs that are unstable in basic environment of distal intestine and colon or those with low solubility at elevated pH conditions (i.e. weak bases). To develop a gastro-retentive delivery system the following steps were taken. First, to investigate the possible incompatibility issues between the model drug and excipients to be used for the delivery system. Stability and physicochemical properties of the active agent and its mixture with excipients were studied using analytical techniques such as Raman spectroscopy and Differential scanning calorimetry (DSC). No incompatibility issues were detected. Second, Kollidon SR as a relatively new release-rate controlling polymer was incorporated in the final formulation. For solid dosage form the ability of the final powder mix to flow well during manufacturing and the intrinsic characteristics that make it compressible are critical. The in-depth compaction study of Kollidon SR was assessed with the help of a compaction simulator. The flowability, swelling and erosion behavior together with release-rate retarding properties of Kollidon SR were also assessed. The final oral delivery system was based on Kollidon SR and Polyethylene Oxide (PEO) 303 as a monolithic matrix system. The noneffervescent monolithic matrix was made by direct compression. In vitro evaluation of the designed system released the active content in a near zero manner. The dosage form was bouyant in pH 2.0 acidic buffer with no floatation lag time which minimizes the possibility of early gastric emptying.
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Nakase, Hiroshi. "Development of an Oral Drug Delivery System Targeting Immune-Regulating Cells in Experimental Inflammatory Bowel Disease ; A New Therapeutic Strategy." Kyoto University, 2001. http://hdl.handle.net/2433/150569.
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Chen, Hongmei 1967. "A novel microencapsulation system : preparation and characterization of genipin cross-linked alginate-chitosan microcapsules for live cell oral delivery and other applications." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=102488.
Full textAbstract:
Oral therapy utilizing artificial cell microencapsulation has shown promise in the treatment of many diseases. The key requirements of microcapsules for such applications include biocompatibility, mechanical stability, permeability and resistance to the human gastrointestinal (GI) environment. In particular, preservation of structural integrity is crucial when live genetically engineered cells are used. One of the main obstacles in the progress of this strategy is attaining biocompatible and stable microcapsules.This thesis aims to develop a suitable microcapsule system, the genipin crosslinked alginate-chitosan (GCAC) microcapsule, for live cell oral delivery. The preparation procedure, including calcium-alginate ionotropic gelation, coacervative chitosan coating and covalent cross-linking by genipin, was established and optimized. Control factors affecting the formation of microcapsule membrane were identified. The structural and physical characteristics of GCAC microcapsules, such as mechanical stability, swelling characteristics, permeability, controlled release, degradation, and others were investigated and compared with earlier established microcapsule systems including alginate-chitosan and alginate-poly-L-lysine-alginate (APA). In addition, live cell oral delivery features were evaluated with a computer controlled dynamic simulated human GI model using genetically engineered Lactobacillus plantarum 80 cells as an example.
Results show that by incorporating genipin, a new class of GCAC microcapsule system can be formulated. Results also show that covalent cross-linking by genipin considerably enhanced the microcapsule stability and durability while maintaining permeability similar to that of the APA membrane. The GCAC membrane possessed strong resistance to structural degradation and GI impediments, while providing a favorable microenvironment for cell proliferation and survival in harsh GI conditions.
In addition, this research found that the fluorogenic attributes of genipin can be exploited to characterize the microcapsule membrane by confocal laser scanning microscopy. A simple, in situ, and non-destructive approach was established and extended to assess other microcapsule systems. Rapid determination of coating material distribution, binding intensity, and membrane thickness on a routine basis was achieved using this novel and superior method.
This work highlights the immense potential of the novel genipin cross-linked alginate-chitosan microcapsule as an oral delivery vehicle for live therapeutic cells and other important applications. Further studies will investigate its full potential for artificial cell oral therapy.
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Hallinan, Robert Michael. "Increasing the Oral Bioaccessibility of Curcumin Using Oleogels Structured by Rice Bran Wax." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1578004597209035.
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Chu, Jacquelene. "Linker-based Lecithin Oral Drug Delivery Systems." Thesis, 2012. http://hdl.handle.net/1807/33716.
Full textAbstract:
In this study, pharmaceutical-grade and food-grade linker-based lecithin self-emulsifying delivery systems (SEDS) were developed with a combination of lipophilic and hydrophilic linkers. These additives at suggested concentrations are safe for pharmaceutical and food applications. The ratio of surfactant lecithin and linkers in these systems was optimized to develop surfactant in oil preconcentrates. The preconcentrates containing different surfactant concentrations and oil were diluted with fed state simulated intestinal fluid to produce pseudo-ternary phase diagrams and to identify the formulations that produced self-emulsifying or self-microemulsifying delivery systems. Optimal SEDS preconcentrates were evaluated using a dialyzer model to simulate intestinal uptake. An uptake of 39.6 mg/cm2 for the pharmaceutical-grade SEDS was obtained within 72 minutes, which promises substantial improvement in the bioavailability of hydrophobic actives. The optimal uptake of 12.2 mg/cm2 for food-grade SEDS suggests enhancement in the bioavailability of omega-3 fatty acids.
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Shaikh, Rubina Perveen. "Oral electrospun multi-component membranous drug delivery systems." Thesis, 2013. http://hdl.handle.net/10539/12533.
Full textAbstract:
Oral drug delivery is perceived by many as the ideal method of drug delivery due to its versatility, ease and
convenience. However, the bioavailability of drugs delivered via the oral route remains questionable.
Typically, conventional marketed drug delivery systems release drugs in variable and erratic fashions, causing
sub-therapeutic or even toxic doses. As a result, patient compliance is threatened, ultimately affecting the
success of the therapeutic intervention. Furthermore, the harsh gastric environment further compromises oral
bioavailability due to the presence of a highly acidic environment and proteolytic enzymes.
A multi-component, membranous drug delivery system (MMDDS) was thus designed, formulated and
evaluated for the site-specific delivery of two (or more) drugs in a prolonged release manner, ultimately easing
complicated treatment regimens, and improving patient compliance. The MMDDS essentially comprises of a
gastric-targeted and an intestinal-targeted component, each containing a protective coat, a drug-loaded layer
incorporating the respective drugs, and a pH-responsive mucoadhesive layer for site-specific mucoadhesion.
The MMDDS employs a combination of controlled and targeted drug release mechanisms, in addition to
gastro-retentive or intestinal retentive mechanisms. Furthermore, the system physically protects the drug
delivery system from acidic or proteolytic degradation within the human gastro-intestinal tract. The present
study employed the use of pH-dependant mucoadhesion for site-specific, segregated and gastroretentive drug
delivery while crosslinking was employed for rate-modulated drug delivery. Rifampicin and isoniazid were
selected as the model drugs in this study as they are known for interacting when administered simultaneously
(detrimentally affecting the bioavailability of rifampicin). Notwithstanding this interaction, rifampicin and
isoniazid must be taken concurrently for successful TB therapy. Therefore these drugs would benefit from the
site-specific drug delivery offered by the MMDDS.
The primary aim of the pH-responsive mucoadhesive layer was to ensure prolonged adhesion of the MMDDS
at a specific site within the human gastro-intestinal tract. The pH-responsive mucoadhesive layer was the
fundamental aspect that promoted site-specific and segregated drug delivery. Preliminary in vitro
investigations led to the identification of a combination of polymers best suited to develop the respective pHresponsive
mucoadhesive layers. A central composite design was employed to determine the optimal ratios of
the polymers selected which would impart the largest degree of mucoadhesion within the respective pH
ranges. Each mucoadhesive layer was thereafter optimized and subject to various in vitro investigations to
determine the effects of the GIT on the properties of the mucoadhesive layer, as well as determine the
behaviour of the mucoadhesive layer when subject to simulated gastrointestinal conditions.
Electrospinning, a versatile technique employed in the fabrication of fibres in the nanometre size range, was
employed to develop the drug loaded layer. Poly(vinyl alcohol) (PVA) nanofibres were thereafter crosslinked
employing glutaraldehyde vapours to ensure controlled release of the incorporated drugs. The drug-loaded
layer demonstrated good versatility in incorporating vastly different drugs, with only minor adjustments to the
fabrication procedure. Furthermore, PVA demonstrated good loading of rifampicin and isoniazid, and near
zero-order drug release was achieved after the crosslinking procedure. Prolongation of drug release
fundamentally decreases the numbers of doses required to be taken daily, and as such, patient compliance is
improved.
Furthermore, in vitro analysis revealed that the developed MMDDS behaved superiorly in terms of controlling
drug delivery in a site-specific and prolonged fashion in comparison to a marketed gold standard formulation,
Rifinah®. These findings were further substantiated by in vivo analysis, which was conducted in a swine
model. Results indicated that minimal release of isoniazid was observed in the stomach, based on the plasma
concentrations of the drug. Release of isoniazid was initiated only when the intestinal-targeted component
entered the intestine of the pig, corresponding to higher plasma concentrations of isoniazid. In this manner,
the delivery of isoniazid and rifampicin was segregated, thus improving the oral bioavailability of rifampicin.
To summarize, the MMDDS was able to overcome the many challenges associated with oral drug delivery, by
easing complicated treatment regimens, and improving the bioavailability of drugs delivered orally. The
benefits associated with oral drug delivery have clearly been exploited by the present study, producing a
versatile drug delivery “tool” which can successfully be adapted to incorporate any number of drugs (including
an entire treatment regimen in one dosage form!) for targeted delivery within the human gastro-intestinal tract
in a prolonged manner.
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Hibbins, Angus Rolland. "An oral ghost delivery device for macromolecules." Thesis, 2015. http://hdl.handle.net/10539/17360.
Full textAbstract:
Recently, there has been an explosion of interest in developing biopharmaceutical
therapeutics for the treatment of life altering conditions. The main issue with the utilization of
biopharmaceutical therapeutics is the mode of administration. The Oral Ghost Drug Delivery
(OGDD) device could potentially enable the administration of these peptide therapeutics via
the oral route and significantly extend the application of these advanced therapeutic
compounds.