Antibiotic therapy has been proven to be vital for the treatment of life-threatening bacterial infections. Oral antibiotic therapy, however, results in unwanted side effects such as the intestinal flora destruction, allowing for the colonization of foreign bacteria. This phenomenon results in the occurrence of antibioticassociated diarrhea. Probiotic supplementation has been the choice adjunctive prophylaxis for this condition allowing for the bacterial adhesion of intestinal mucosal binding sites. Probiotic bacteria are, however, susceptible to the bactericidal effects of broad-spectrum antibiotics, resulting in many probiotic formulations being prescribed two hours after the ingestion of the antibiotic formulation. This is, however, not always adhered to, with many patients taking the antibiotic and probiotic concomitantly resulting in the destruction of the probiotic bacteria. This study provides for the design, development, characterization and evaluation of an oral delivery system for the concurrent administration of antibiotics and probiotics employing a dual release mechanism or ‘Dual-Biotic System’. The premise behind the development of this system is to allow for the concurrent administration of antibiotics and probiotics where the probiotic bacteria are only released two hours after the antibiotic, in which time the antibiotic would be absorbed into systemic circulation, preventing physical interaction between the systems and thus preventing bacterial destruction. Amoxicillin was chosen as the model antibiotic in this study due to its spectrum of activity and wide utilization in oral antibiotic therapy.

Thesis (Ph. D.)--University of Washington, 1992. / Vita. Includes bibliographical references (leaves [210]-240).

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves 158-173).

Ces travaux visaient à développer de nouveaux implants biodégradables se formant in situ pour le traitement des parodontites, les infections les plus fréquentes au monde. Ces implants permettront de délivrer localement le principe actif et de contrôler sa libération. L’un des pré-requis pour ces nouveaux systèmes est de présenter une bonne bioadhésion et des propriétés mécaniques permettant d’éviter une expulsion prématurée hors de la poche parodontale.Tout d’abord, de nouveaux implants se formant in situ avec un potentiel prometteur pour surmonter l'un des inconvénients majeurs liés au traitement local de la parodontite: l’adhérence limitée aux tissus environnants ont été développés. L'addition de diverses concentrations de différents types de plastifiants (l’acetyltributyl citrate, ATBC et le dibutyl sebacate, DBS) et de polymères adhésifs (l'hydroxypropyl méthylcellulose, HPMC) ont permis d’obtenir une augmentation significative de l’adhésion des implants à base de l’acide poly(lactique-co-glycolique) (PLGA). Ces systèmes sont formés in situ à partir des formulations liquides de N-méthyl-2-pyrrolidone (NMP). Dans le même temps, une bonne aptitude à la déformation plastique des implants a été obtenue et les cinétiques de libération du principe actif souhaitées ont pu être affinées à l'aide de plusieurs outils de formulation. L'activité antimicrobienne de ce nouveau type d'implants se formant in situ, chargés à l’hyclate de doxycycline, a été démontrée en utilisant la méthode de diffusion en gélose sur plusieurs souches de Streptococcus isolées à partir de la microflore buccale des patients souffrant de parodontite.Ensuite, une meilleure compréhension des mécanismes de formation in situ des implants a été suivi en utilisant de différentes techniques tels que: la résonance paramagnétique électronique (EPR), la résonance magnétique nucléaire (1H NMR), le suivi de l’évolution de la masse et la cinétique de libération du principe actif dans différentes conditions, la microscopie optique, la chromatographie d'exclusion stérique (SEC). Des implants se formant in situ à base de PLGA, d’ATBC, de chlorhydrate de minocycline, de NMP et d’HPMC, ont été préparés et caractérisés en détail in vitro. Ces résultats ont révélé une vision approfondie sur les phénomènes physico-chimiques impliqués dans la formation de l'implant et sur le contrôle de la libération du principe actif. Par exemple, les effets de l'ajout d’HPMC dans la formulation, qui améliore l'adhérence de l'implant et réduit le gonflement, ont pu être expliqués. De manière importante, les implants se formant in situ ont efficacement empêché la croissance bactérienne dans les poches parodontales des patients. Enfin, l’impact de la composition des implants sur la performance des systèmes a été étudié. Afin d’élucider ces relations, des techniques de caractérisation de pointe, telles que l'analyse EPR ont été utilisées. Il est intéressant de noter que l’ajout d’HPMC et de PLGA de plus faible poids moléculaire a légèrement diminué la libération du principe actif, alors que dans le cas de PLGA de poids moléculaire plus élevé, la vitesse de libération a substantiellement augmenté. Ces tendances peuvent être expliquées en se basant sur la cinétique du transport de masse au cours de la formation de l'implant et des structures internes des systèmes. En outre, l'activité antimicrobienne des implants contre les micro-organismes présents dans les poches parodontales de patients atteints de parodontite a été évaluée. Ces systèmes gênent plus efficacement la croissance des bactéries pathogènes que celle des micro-organismes physiologiques. Ainsi, une recolonisation de la flore saine dans les poches des patients peut être envisagée in vivo. / This work aimed to develop new biodegradable in situ forming implants for the treatment of periodontitis, the most common infections in the world. These implants would locally deliver the active ingredient and control its release. One of the prerequisites for these new systems is to provide a good bioadhesion and mechanical properties to prevent premature expulsion from the periodontal pocket. Firstly, new in situ forming implants with promising potential to overcome one of the major drawbacks for the local treatment of periodontitis: limited adhesion to the surrounding tissue were developed. The addition of various concentrations of different types of plasticizers (acetyltributyl citrate, ATBC and dibutyl sebacate, DBS) and adhesive polymers (hydroxypropyl methylcellulose, HPMC) resulted in a significant increase in the adhesion of poly(lactic-co-glycolic acid) (PLGA)-based implants. The systems are formed in situ from N-methyl pyrrolidone (NMP)-based liquid formulations. Importantly, at the same time, good plastic deformability of the implants could be provided and desired drug release patterns could be fine-tuned using several formulation tools. The antimicrobial activity of this new type of in situ forming implants, loaded with doxycycline hyclate, was demonstrated using the agar well diffusion method and multiple Streptococcus strains isolated from the oral microflora of patients suffering from periodontitis.Secondly, a better understanding of the mechanisms of the in situ implant formation was followed using different techniques such as electron paramagnetic resonance (EPR), nuclear magnetic resonance (1H NMR), mass change and drug release measurements under different conditions, optical microscopy, size exclusion chromatography (SEC). The in situ forming implants containing PLGA, ATBC, minocycline hydrochloride, HPMC and NMP were prepared and characterized in detail in vitro. Based on these results, deeper insight into the physico-chemical phenomena involved in implant formation and the control of drug release could be gained. For instance, the effects of adding HPMC to the formulations, resulting in improved implant adherence and reduced swelling, could be explained. Importantly, the in situ formed implants effectively hindered the growth of bacteria present in the patients’ periodontal pockets.Finally, the impact of the composition of the implants on system performance was investigated using advanced characterization techniques, such as EPR analysis. Interestingly, HPMC addition to shorter chain PLGA slightly decreased drug release, whereas in the case of longer chain PLGA the release rate substantially increased. These tendencies could be explained based on the mass transport kinetics during implant formation and the systems’ inner structures. Furthermore, the implants’ antimicrobial activity against microorganisms present in the periodontal pockets of patients suffering from periodontitis was evaluated. Interestingly, these systems more effectively hinder the growth of pathogenic bacteria than of physiological microorganisms. Thus, a re-colonization of the patients’ pockets with healthy flora can be expected to be favored in vivo.

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves [95]-100).

Submitted by Haroudo Xavier Filho (haroudo.xavierfo@ufpe.br) on 2016-04-14T18:22:12Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação -Marciana S_ F_ Cordeiro _1_.certa.pdf: 3647564 bytes, checksum: f459470e06543d55f9f637a82005d075 (MD5) / Made available in DSpace on 2016-04-14T18:22:12Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação -Marciana S_ F_ Cordeiro _1_.certa.pdf: 3647564 bytes, checksum: f459470e06543d55f9f637a82005d075 (MD5) Previous issue date: 2015-02-25 / CNPq / O cloridrato de pilocarpina vem sendo utilizado no tratamento da xerostomia, entretanto sua atuação sistêmica promove reações adversas indesejáveis. Contudo, os atuais sistemas de liberação prolongada de fármacos, podem controlar variações de concentração plasmática e reduzir estes efeitos colaterais. Adicionalmente, a obtenção de comprimidos mucoadesivos associado a este sistema de liberação favorece a ação prolongada do fármaco na cavidade oral, trazendo benefícios importantes para o tratamento. Assim, este trabalho tem como objetivo o desenvolvimento de comprimidos mucoadesivos a base de cloridrato de pilocarpina para o tratamento da xerostomia, utilizando para este propósito a mistura física da goma do cajueiro/pilocarpina, quitosana/pilocarpina, mistura física de ambos os polímeros com pilocarpina e desenvolvimento de uma blenda polimérica por liofilização contendo goma de cajueiro e quitosana. Inicialmente a compatibilidade fármaco-polímero foi avaliada através da Calorimetria Exploratória Diferencial (DSC), Termogravimetria (TG), Espectroscopia de Infravermelho (IV) e Difração de Raios-X (DRX). Em seguida, foram obtidos comprimidos por compressão direta. Os comprimidos obtidos foram submetidos ao controle de qualidade, avaliação mucoadesiva e perfil de liberação. Na avaliação da mistura física (MF) dos polímeros/pilocarpina e da blenda/pilocarpina não foram encontrados sinais de incompatibilidades diante da avaliação pelas técnicas de DSC e TG. Dentre as formulações desenvolvidas, a blenda/pilocarpina demonstrou agregar propriedades mucoadesivas e retardo na liberação do fármaco, propriedades estas não encontradas nos polímeros individualmente e na mistura física/pilocarpina. A blenda/pilocarpina apresentou liberação de 53% do fármaco no tempo 180 min., tempo de mucoadesão de 510 min e incremento da força de mucoadesão. Esses resultados mostram o potencial do sistema polimérico para futuros desenvolvimentos na área farmacêutica. / The pilocarpine hydrochloride has been used in the treatment of xerostomia, however its systemic activity promotes undesirable side effects. However, the current prolonged release of drugs can control variations in plasma concentration and reduce these side effects. Additionally, to obtain tablets mucoadhesive associated with this delivery system favors prolonged drug action in oral cavity, which has important benefits for treatment. This work aims to develop mucoadhesive tablets pilocarpine hydrochloride base for the treatment of xerostomia, using for this purpose the physical mixture of cashew gum/pilocarpine, chitosan/pilocarpine, physical mixture of both polymers with pilocarpine and development of a polymer blend by lyophilization containing cashew gum and chitosan. Initially the drug-polymer compatibility was evaluated by Differential Scanning Calorimetry (DSC), thermogravimetry (TGA), Infrared Spectroscopy (IR) and X-ray Diffraction (XRD). Then, tablets were obtained by direct compression. The tablets were subjected to quality control, mucoadhesive evaluation and release profile. In assessing the physical mixture (MF) of the polymers / pilocarpine and blend / pilocarpine were not incompatible signals found on the evaluation by DSC and TG techniques. Among the developed formulations, the blend / pilocarpine shown add mucoadhesive properties and delayed drug release, these properties not found in polymers individually and physical / pilocarpine mixture. The blend / pilocarpine showed 53% release of the drug in time 180 min. Mucoadhesion time of 510 min, and increased strength mucoadhesion. These results show the potential of the polymer system for future developments in the pharmaceutical field.

Zhang, Xinran. / Thesis submitted in: December 2007. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 80-87). / Abstracts in English and Chinese. / TITLE PAGE --- p.i / ABSTRACT --- p.ii / 中文摘要 --- p.v / ACKNOWLEDGEMENTS --- p.vii / TABLE OF CONTENTS --- p.viii / LIST OF FIGURES --- p.xi / LIST OF TABLES --- p.xiv / ABBREVIATIONS --- p.xv / Chapter CHAPTER 1. --- Introduction / Chapter 1.1. --- Rationale of the Study --- p.1 / Chapter 1.2. --- Current technologies for formulating long-acting parenteral protein deliver system --- p.3 / Chapter 1.2.1. --- Chemical Modification --- p.3 / Chapter 1.2.2. --- Sustained-release formulation --- p.4 / Chapter 1.2.2.1. --- Phase separation method --- p.4 / Chapter 1.2.2.2. --- Solvent evaporation/extraction method --- p.5 / Chapter 1.2.2.3. --- Spray drying method --- p.6 / Chapter 1.2.2.4. --- Causes for protein instability --- p.6 / Chapter 1.2.2.4.1. --- Water/organic solvent interface --- p.6 / Chapter 1.2.2.4.2. --- Lyophilization --- p.8 / Chapter 1.2.2.4.3. --- Polymer --- p.11 / Chapter 1.2.2.4.4. --- Stabilizing additive --- p.13 / Chapter 1.3. --- Aqueous-aqueous emulsion technology --- p.17 / Chapter 1.3.1. --- Background --- p.17 / Chapter 1.3.2. --- Basic Principle --- p.17 / Chapter 1.3.3. --- Phase diagram --- p.18 / Chapter 1.3.4. --- Formation of aqueous-aqueous emulsion --- p.19 / Chapter 1.3.4.1. --- Introduction of a water-soluble charged polymer as stabilizer --- p.19 / Chapter 1.3.4.2. --- Freezing-induced phase separation --- p.20 / Chapter 1.3.5. --- General Protocol --- p.21 / Chapter 1.3.5.1. --- Introduction of a water-soluble charged polymeric stabilizer --- p.22 / Chapter 1.3.5.2. --- Freezing-induced phase separation --- p.22 / Chapter 1.3.6. --- Merits and limitations of the aqueous-aqueous emulsion technology --- p.23 / Chapter 1.3.7. --- Protein selection for the sustained release formulation --- p.25 / Chapter 1.4. --- Aims and scope of study --- p.26 / Chapter "CHAPTER 2," --- Materials and Methods / Chapter 2.1. --- Materials --- p.28 / Chapter 2.1.1. --- Proteins --- p.28 / Chapter 2.1.2. --- Polymers --- p.28 / Chapter 2.1.3. --- Media for TF-1 Cell Culture --- p.28 / Chapter 2.1.4. --- Chemicals and Solvents for Cell Proliferation Assay --- p.29 / Chapter 2.1.5. --- Other Chemicals and Solvents --- p.29 / Chapter 2.1.6. --- Materials for Cell Culture --- p.29 / Chapter 2.1.7. --- Materials for Reagent Kits --- p.30 / Chapter 2.2. --- Methods --- p.30 / Chapter 2.2.1. --- Determination of the Partition Coefficients of Proteins Between PEG and Dextran --- p.30 / Chapter 2.2.2. --- Preparation of Glassy Particles --- p.31 / Chapter 2.2.2.1. --- Standard Stable Aqueous-aqueous Emulsion Method --- p.31 / Chapter 2.2.2.2. --- Freezing-induced Phase Separation --- p.32 / Chapter 2.2.3. --- Preparation of Protein-loaded and Blank Microspheres Using S-o-w Solvent Extraction Technique --- p.32 / Chapter 2.2.4. --- Optical Microscopy and Scanning Electron Microscopy --- p.33 / Chapter 2.2.5. --- Determination of Protein Loading --- p.34 / Chapter 2.2.5.1. --- Within Dextran Particles --- p.34 / Chapter 2.2.5.2. --- Within PLGA microspheres --- p.34 / Chapter 2.2.6. --- Evaluation of Protein Structural Integrity and Bioactivity in Dextran Particles and PGLA Microspheres --- p.35 / Chapter 2.2.7. --- In vitro Release Study --- p.36 / Chapter 2.2.8. --- RhIFN Stability Determination under Simulated In Vitro Release Conditions --- p.37 / Chapter 2.2.8.1. --- In the Absence of PLGA --- p.37 / Chapter 2.2.8.2. --- In the Presence of PLGA --- p.37 / Chapter 2.2.9. --- MicroBCÁёØ Protein Assay --- p.38 / Chapter 2.2.10. --- Size Exclusion Chromatography (SEC) - High Performance Liquid Chromatography (HPLC) --- p.38 / Chapter 2.2.11. --- ELISA --- p.39 / Chapter 2.2.12. --- Bioactivity Assay --- p.40 / Chapter 2.2.12.1. --- RhIFN --- p.40 / Chapter 2.2.12.2. --- RhGM-CSF --- p.41 / Chapter CHAPTER 3. --- Results and Discussions / Chapter 3.1. --- Sustained-release RhIFN Formulation --- p.45 / Chapter 3.1.1. --- Partition Coefficient of RhIFN --- p.45 / Chapter 3.1.2. --- Formulation Based on the Standard Aqueous-aqueous Emulsion (SA-AE) Method With Sodium Alginate as Stabilizer --- p.45 / Chapter 3.1.2.1. --- Surface Morphology --- p.45 / Chapter 3.1.2.2. --- Formulation Characterization --- p.46 / Chapter 3.1.2.3. --- In Vitro Release of RhIFN from PLGA Microsheres --- p.54 / Chapter 3.1.3. --- Formulation Based on the Freezing-induced Phase Separation (FIPS) Technique without Sodium Alginate --- p.56 / Chapter 3.1.3.1. --- Formulation Characterization --- p.56 / Chapter 3.1.3.2. --- In Vitro Release of RhIFN from PGLA Microsphees --- p.59 / Chapter 3.2. --- RhIFN Stability Assessment under Simulated In Vitro Release Conditions --- p.63 / Chapter 3.2.1. --- In the Absence of PLGA --- p.63 / Chapter 3.2.2. --- In the Presence of PLGA --- p.65 / Chapter 3.3. --- Sustained-release RhGM-CSF Formulation --- p.68 / Chapter 3.3.1. --- Partition Coefficient Determination of RhGM-CSF Between PEG and Dextran --- p.68 / Chapter 3.3.2. --- Formulation Based on Freezing-induced Phase Separation --- p.68 / Chapter 3.3.2.1. --- Validation of MTT Assay Conditions --- p.69 / Chapter 3.3.2.2. --- Formulation Characterization --- p.71 / Chapter 3.3.2.3. --- In Vitro Release of RhGM-CSF from PLGA Microspheres --- p.75 / Chapter CHAPTER 4. --- Conclusion and Future Studies / Chapter 4.1. --- Conclusion --- p.78 / Chapter 4.2. --- Future Studies --- p.79 / References --- p.80

Thesis (M.Sc.), Memorial University of Newfoundland, School of Pharmacy, / Typescript. Bibliography: p. 141-166.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Yes / A new type of self-assembled polyelectrolyte complex nanocarrier composed of chondroitin (CHON) and protamine (PROT) was designed and the ability of the carriers to bind salmon calcitonin (sCT) was examined. The response of sCT-loaded CHON/PROT NPs to a change in the properties of the liquid medium, e.g. its pH, composition or ionic strength was studied and in vitro peptide release was assessed. The biocompatibility of the NPs was evaluated in Caco-2 cells. CHON/PROT NPs were successfully obtained with properties that were dependent on the concentration of the polyelectrolytes and their mixing ratio. X-ray diffraction determined the amorphous nature of the negatively charged NPs, while those with the positive surface potential were semi-crystalline. sCT was efficiently associated with the nanocarriers (98-100%) and a notably high drug loading (13-38%) was achieved. The particles had negative zeta potential values and were homogenously dispersed with sizes between 60 and 250 nm. CHON/PROT NPs released less than 10% of the total loaded peptide in the first hour of the in vitro release studies. The enthalpy of the decomposition exotherm correlated with the amount of sCT remaining in NPs after the release experiments. The composition of medium and its ionic strength was found to have a considerable influence on the release of sCT from CHON/PROT NPs. Complexation to CHON markedly reduced the toxic effects exerted by PROT and the NPs were compatible and well tolerated by Caco-2 cells.