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A polyelectrolyte complex is formed by mixing two oppositely charged polyelectrolytes in a solution. The electrostatic interactions between partially charged polymeric chains lead to the formation of a stable complex while avoiding the use of covalent cross linkers. Since complex formation can improve the stability of polyelectrolyte and metal ions in polyelectrolyte can provide various functionalities, PECs incorporated with metal ions are promising candidates for manufacturing stable and multifunctional structures. While the coordination of metal ions and polyelectrolytes has been extensively investigated in solutions and multilayer films, to our knowledge, no research has been performed to study the effect of metal ion/polyelectrolyte interactions on PECs structures and properties. The following research demonstrates the impact of different metal ions in controlling PEC structure morphology and applications. These discoveries indicate great potential of metal ions in PECs to fabricate functional PEC nanostructures. The research investigates the effect of the interactions between different metal ions and polyelectrolytes on the morphology and properties of PECs, explore the fabrication of different structures using embedded metal ions and understand the impact of metal ion/polyelectrolyte interactions on the nanoparticle structures. The research concludes: 1) incorporating metal ions of different valence into PECs introduces metal ion/polyelectrolyte interactions that can tune the morphology of PECs; 2) metal ion/polyelectrolyte interactions can be used to control the PECs swelling properties and stability in aqueous solutions; 3) the release of embedded metal ions from PECs to aqueous solutions is affected by metal ion/polyelectrolyte interactions; and 4) the embedded metal ions function as a reagent reservoir for various applications to produce functional structures.

Yes / The aim of this work was to investigate the possibility of covalent cross-linker-free, polyelectrolyte complex formation at the nanoscale between alginic acid (as sodium alginate, ALG) and protamine (PROT). Optimisation of the self-assembly conditions was performed by varying the type of polymer used, pH of component solutions, mass mixing ratio of the components and the speed and order of component addition on the properties of complexes. Homogenous particles with nanometric sizes resulted when an aqueous dispersion of ALG was rapidly mixed with a solution of PROT. The polyelectrolyte complex between ALG and PROT was confirmed by infrared spectroscopy. To facilitate incorporation of drugs soluble at low pH, pH of ALG dispersion was decreased to 2; however, no nanoparticles (NPs) were formed upon complexation with PROT. Adjusting pH of PROT solution to 3 resulted in the formation of cationic or anionic NPs with a size range 70–300 nm. Colloidal stability of selected alginic acid low/PROT formulations was determined upon storage at room temperature and in liquid media at various pH. Physical stability of NPs correlated with the initial surface charge of particles and was time- and pH-dependent. Generally, better stability was observed for anionic NPs stored as native dispersions and in liquids covering a range of pH. / This study was funded by Merrion Pharmaceuticals Ireland. This work was also supported by the Synthesis and Solid State Pharmaceutical Centre funded by the Science Foundation Ireland under grant number 12/RC/2275.

No / This work investigates a new type of polyelectrolyte complex nanocarrier composed of hyaluronic acid (HA) and protamine (PROT). Small (approximately 60 nm) and negatively charged nanoparticles (NPs) with a polydispersity index of less than 0.2 were obtained with properties that were dependent on the mixing ratio, concentration of polyelectrolytes and molecular weight of HA. Salmon calcitonin (sCT) was efficiently (up to 100%) associated with the NPs, and the drug loading (9.6-39% w/w) was notably high, possibly due to an interaction between HA and sCT. The NPs released ~70-80% of the sCT after 24 hours, with the estimated total amount of released sCT depending on the amount of HA and PROT present in the NPs. The isoelectric point of the NPs was close to pH 2, and the negative surface charge was maintained above this pH. The HA/PROT nanoplexes protected the sCT from enzymatic degradation and showed low toxicity to intestinal epithelial cells, and thus may be a promising oral delivery system for peptides.

Polyelectrolyte complexes (PECs) between chitosan, a mucoadhesive, intestinal mucosal permeability-enhancing polysaccharide, and cellulose nanocrystals, rod-like cellulose nanoparticles with sulfate groups on their surface, have potential applications in oral drug delivery. The purpose of this research was to develop an understanding of the formation and properties of chitosan–cellulose nanocrystal PECs and determine their in vitro drug release properties, using caffeine and ibuprofen as model drugs. Cellulose nanocrystals were prepared by sulfuric acid hydrolysis of bleached wood pulp. Chitosans with three different molecular weights (81, 3·103, 6·103 kDa) and four different degrees of deacetylation (77, 80, 85, 89%) were used. PEC formation was studied by turbidimetric titration. PEC particles were characterized by FT-IR spectroscopy, scanning electron microscopy, dynamic light scattering, and laser Doppler electrophoresis. The formation and properties of chitosan–cellulose nanocrystal PEC particles were governed by the strong mismatch in the densities of the ionizable groups. The particles were composed primarily of cellulose nanocrystals. Particle shape and size strongly depended on the mixing ratio and pH of the surrounding medium. The ionic strength of the surrounding medium, and the molecular weight and degree of deacetylation of chitosan had a minor effect. Release of caffeine from the chitosan–cellulose nanocrystal PEC particles was rapid and uncontrolled. Ibuprofen-loaded PEC particles showed no release in simulated gastric fluid and rapid release in simulated intestinal fluid. Further evaluation studies should focus on the expected mucoadhesive and permeability-enhancing properties of chitosan–cellulose nanocrystal PEC particles. / Ph. D.

Active Pharmaceutical Ingredients with poor solubility have presented significant difficulties in drug product design and development including slow and ineffective absorption leading to inadequate and variable bioavailability. Therefore it has become increasingly desirable to overcome the low aqueous solubility of drug candidates and develop more novel and innovative formulation approaches to increase the dissolution rate of the poorly soluble drugs. This work focuses on the formulation of novel amorphous ibuprofen-polymer nanoconjugates based on the polymer-drug complexation in order to improve its physical and dissolution characteristics without the use of toxic organic solvents. Plain and ibuprofen-loaded binary and ternary nanoconjugates were prepared using four modified co-precipitation techniques including melt solubilization; alkaline solubilization; surfactant solubilization and hydrotropic complexation techniques. A remarkably high loading capacity was achieved ranging from 89.05 to 99.49% across the four techniques and polymer-polymer ratio of 50:50 was found to be most efficient. All the four techniques reduced the size of ibuprofen (2.87 μm) significantly in the presence of 2.0 x10-3 mM of Diethylaminoethyl Dextran (DEAE-Dextran) in the order melt solubilization (203.25 nm) > alkaline solubilization (185.68 nm) > surfactant (Tween 80) solubilization (122.17 nm) > hydrotropic complexation (77.92 nm). 5.0 x 10-4 mM of chitosan also reduced the size of ibuprofen from 2872.12 to 10.70 nm (268-fold reduction). The FTIR spectroscopic analysis revealed electrostatic, hydrophobic and hydrogen bonding interaction between solubilized ibuprofen and the cationic polymers (DEAE-Dextran and chitosan) to form a new product (an amide). Polymer-polymer complexation also occurred between DEAE-Dextran and gellan as well as chitosan and gellan to a different extent depending on the mixing ratios. 1H and 13C NMR analysis confirmed the conjugation between ibuprofen and each of the cationic polymers as well as the formation of a new amide product. DSC thermal analysis showed that the nanoconjugates exhibited new broad and diffuse peaks confirming that they did exist in amorphous state as multiple complexes. The TGA thermograms of the binary nanoconjugates exhibited one step degradation profile compared with the physical mixture which exhibited two steps. However the ternary nanoconjugates exhibited two steps degradation profile confirming the formation of multiple complexes. Marked enhancement of drug release was achieved by the four techniques compared with the ibuprofen control. All the DG (DEAE-Dextran - Gellan) complexes exhibited a higher release profile than ibuprofen control. Fickian and non-Fickian anomalous mechanisms were deduced for the drug release of ibuprofen from the binary conjugates. The ternary nanoconjugates exhibited non-Fickian (anomalous) diffusion, Fickian diffusion and Super Case II transport release mechanisms. The ternary nanoconjugate hydrogels exhibited complete release (100%) within 48 h. The lowest concentration of DEAE-Dextran, Gellan - Ibuprofen - DEAE-Dextran (GIbDD) 2:0.125, increased the release of ibuprofen by 13.4% however higher concentrations of DEAE-Dextran decreased the release profile steadily. It was concluded that DEAE-Dextran has potentials in the formulation of modified (extended) release of ibuprofen. The most prominent mechanism of release of ibuprofen from the nanoconjugate hydrogel was Super Case II transport. SEM and AFM micrographs of the drug loaded composite pharmaceutical films exhibited concentric spheres with two and three layers for the binary and ternary films respectively. This supports the evidence of internalization of ibuprofen by the polyelectrolyte complex. The FTIR and DSC results confirmed electrostatic and hydrophobic interactions between ibuprofen and DEAE-Dextran as well as between gellan and DEAE-Dextran. Thermal analysis revealed that plain bilayer films were thermally more stable than composite films. The addition of ibuprofen significantly increased (p < 0.05, n = 4) the swelling ratio of the films compared with films without the drug. The drug loaded bilayer films exhibited Fickian diffusion mechanism while the dominating mechanism for composite films was anomalous (Non-Fickian) transport. From the foregoing, it was evident that ibuprofen-polymer nanoconjugate present a novel tool for the delivery of ibuprofen with potential application for transdermal delivery.

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Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-10-17T13:31:20Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) JANIRA DISSERTAÇÃO PPGIT UFPE 2016.pdf: 2767067 bytes, checksum: c6f9b4694fc912f845955ae3a11a3c37 (MD5) / Made available in DSpace on 2016-10-17T13:31:20Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) JANIRA DISSERTAÇÃO PPGIT UFPE 2016.pdf: 2767067 bytes, checksum: c6f9b4694fc912f845955ae3a11a3c37 (MD5) Previous issue date: 2016-03-15 / CNPq / O desenvolvimento de sistemas de administração de fármacos utilizando biopolímeros, como a goma de cajueiro e quitosana tem-se destacado pela formação de nanoestruturas por complexação polieletrolítica, realizada pela interação das diferentes cargas dos materiais e devido as suas promissoras propriedades, dentre elas: excelente biodegradabilidade, elevada biocompatibilidade, baixa toxicidade. Usados no desenvolvimento nanotecnológico de formulações para proteção de fármacos peptídicos, como a insulina, para sua administração por via oral, no qual faz-se necessário pela sua instabilidade em variações de pH. Este trabalho teve como objetivo a síntese de nanopartículas a partir de biopolímeros por complexação polieletrolítica para administração oral de insulina e avaliação analítica do fármaco e seu principal produto de degradação o A-21 em meio ácido. Nanopartículas de goma de cajueiro e quitosana foram sintetizadas por complexação polieletrolítica com e sem adição do tripolifosfato de sódio, como agente de reticulação. Foram caracterizadas quanto ao seu tamanho, carga superficial, índice de polidispersão e adicionalmente a Espectroscopia da Região do Infravermelho (FTIR), Microscopia Eletrônica de Varredura (MEV), Análise Termogravimétrica (TG). Para a determinação analítica da insulina e seu principal produto de degradação o A-21 foi realizado um planejamento experimental fatorial, a fim de analisar quais variantes iriam influenciar para obtenção de um menor tempo de análise das moléculas por HPLC. Vinte e sete experimentos foram realizados e destacou-se dentre os valores observados nos tempos de retenção de 5,18 min para insulina e 9,10 min para o A-21, na condição onde a temperatura da coluna foi de 35°C, fluxo do eluente de 1,0 mL/min-1 e na proporção da fase móvel de 52% KH2PO4, 31% acetonitrila e 17% metanol, uma análise final com cerca de 11 minutos. Em média os fatores que mais influenciaram no sistema foram o fluxo do eluente e a proporção da fase móvel, demonstrados através da estimativa dos efeito, análise da variância e teste F. O modelo linear obtido demonstrou ter uma boa predição para o método, com pontos reais de distribuição aleatórios condizentes aos resultados obtidos experimentalmente, a variância total explicada de 91,14% e o modelo deixa de explicar 8,86% dos resíduos. A adequabilidade cromatográfica da combinação das variáveis independentes resultaram em valores próximos ou dentro dos limites estabelecidos. Os resultados das avaliações de concentração dos biopolímeros, proporção dos agentes de reticulação, ordens de adição, pH das soluções mostraram-se bastante significativos na influência dos tamanhos das partículas, potencial zeta e índice de polidispersão. Houve uma grande distinção das preparações com e sem TPP, pois foi evidenciada uma eficaz ação reticulante entre os polieletrólitos, as ligações cruzadas realizadas foram importantes para aperfeiçoamento dos parâmetros, demonstrado a redução dos tamanhos das nanopartículas, de modo homogêneo e com baixos índices de polidispersão, potenciais zeta na faixa neutra diferindo nos valores de acordo com a concentração adicionado. Através das caracterizações realizadas por FTIR, MEV e TG houve a demonstração da interação entre os materiais estudados. As características e propriedades apresentadas pelas nanoesferas formadas pela interação GC/TPP/QT indicam um promissor sistema de liberação de fármacos e proteção para moléculas instáveis ao ambiente gastrointestinal. / The development of drug delivery systems using biopolymers such as cashew gum and chitosan it has been highlighted by the formation of nanostructures by complexation polyelectrolytic held by the interaction of the different loads of materials and due to their promising properties, among them: excellent biodegradability , high biocompatibility, low toxicity. Used in nanotechnological development of formulations for protection peptide drugs such as insulin, for administration orally, in which it is necessary for its instability at pH variations. This study aimed to the synthesis of nanoparticles from biopolymers by complexation polyelectrolytic for oral administration of insulin and analytical evaluation of the drug and its main degradation product A-21 in acid. cashew gum and chitosan nanoparticles were synthesized by complexation polyelectrolytic with and without addition of sodium tripolyphosphate as crosslinking agent. They were characterized as to their size, surface charge, polydispersity and additionally Spectroscopy Infrared Region index (FTIR), Scanning Electron Microscopy (SEM), Thermogravimetric Analysis (TG). For the analytical determination of insulin and its main degradation product A-21 factorial experimental design was conducted to analyze variants which would influence to obtain a shorter analysis of molecules by HPLC. Twenty-seven experiments were conducted and it was highlighted among the values observed at 5.18 min retention time of 9.10 min for insulin and A-21 in the condition where the column temperature was 35 ° C, flow of the eluent of 1.0 ml / min-1 and the rate of mobile phase of 52% KH2PO4, 31% acetonitrile and 17% methanol, with a final analysis about 11 minutes. On average the factors that most influence the system were the eluent flow and the proportion of the mobile phase, demonstrated by estimating the effect of variance analysis and test F. The resulting linear model was shown to have a good prediction for the method, with points real random distribution consistent with the results obtained experimentally, the total explained variance of 91.14% and the model fails to explain 8.86% of the waste. Chromatographic suitability of the combination of the independent variables resulted in close to or within the established limits. The results of evaluations concentration of biopolymers, the proportion of cross-linking agents, addition orders, the solutions pH were quite significant in the influence of particle size, zeta potential and molecular weight distribution index. There was distinction of preparations with and without TPP, as was evidenced effective action crosslinking of polyelectrolytes, cross-connections made were important for improvement of the parameters shown to reduce the size of the nanoparticles, homogeneous way and with low levels of polydispersity, zeta potential in the neutral range in differing values according to the concentration added. Through the characterizations made by FTIR, SEM and TG was the demonstration of the interaction between the studied materials. The characteristics and properties presented by the nanospheres formed by the interaction GC / TPP / QT indicate a promising system of drug delivery and protection for unstable molecules to the gastrointestinal environment.