Drug re-engineering is an effective method for engineering existing products in alternative dosage forms and with enhanced pharmacokinetics. Insulin for the management of diabetic symptoms is an ideal candidate for re-engineering. Current subcutaneous therapy results in low patient compliance and is ineffective in meeting the physiological need for post-prandial insulin. Implementation of dose titration for more efficient blood-glucose management is also inconvenient and uncomfortable. Inhaled insulin is presented as a superior alternative to current therapy. The lungs offer excellent access to the circulatory system. Aerosols suspended in inspired air may deposit on lung epithelia and be available for systemic absorption. To evade the defense mechanism of the human respiratory tract, particle sizes have traditionally been minimized to achieve necessary aerosol performance. Recent developments indicate that more efficient performance augmentation may also be achieved by decreasing the bulk density of powders and modifying surface characteristics. Light and fluffy powders with rough surfaces experience much higher drag forces within an airstream. The Atomized Rapid Injection for Solvent Extraction (ARISE) process is a unique precipitation platform devised by incorporating a rapid injection technique for energetic solution delivery into supercritical fluid (SCF) media to effect recovery of previously dissolved pharmaceutical compounds. The quasi-instantaneous delivery of solutions alleviates the drawbacks of the use of capillary nozzles or micro-orifices, gradual elution and mixing controlled precipitation kinetics in existing SCF precipitation techniques. Most importantly, the energetic release of solution into SCF media effects supersaturation over a much larger spatial volume and promotes the homogeneous precipitation of low bulk density powders. ARISE processed insulin powders displayed characteristics that were highly influenced by anti-solvent conditions and powders of different qualities were obtained as a function of anti-solvent pressures. At lower anti-solvent pressures, powders of narrow particle size distribution were achieved, an indication of homogeneous supersaturation levels within processing. Span, the index of size distribution was as low as 0.991. At higher anti-solvent pressures, supersaturation rates were increased while mixing efficiencies decreased, resulting in powders of wider size distribution, and powder bulk densities as low as 0.01 g/ml. Low bulk density insulin displayed in-vitro respirable fractions as high as 78%.

University of Macau / Institute of Chinese Medical Sciences

Thesis (Ph. D.)--University of Texas at Austin, 2000. / Vita. Includes bibliographical references (leaves 166-173). Available also in a digital version from Dissertation Abstracts.

Drug re-engineering is an effective method for engineering existing products in alternative dosage forms and with enhanced pharmacokinetics. Insulin for the management of diabetic symptoms is an ideal candidate for re-engineering. Current subcutaneous therapy results in low patient compliance and is ineffective in meeting the physiological need for post-prandial insulin. Implementation of dose titration for more efficient blood-glucose management is also inconvenient and uncomfortable. Inhaled insulin is presented as a superior alternative to current therapy. The lungs offer excellent access to the circulatory system. Aerosols suspended in inspired air may deposit on lung epithelia and be available for systemic absorption. To evade the defense mechanism of the human respiratory tract, particle sizes have traditionally been minimized to achieve necessary aerosol performance. Recent developments indicate that more efficient performance augmentation may also be achieved by decreasing the bulk density of powders and modifying surface characteristics. Light and fluffy powders with rough surfaces experience much higher drag forces within an airstream. The Atomized Rapid Injection for Solvent Extraction (ARISE) process is a unique precipitation platform devised by incorporating a rapid injection technique for energetic solution delivery into supercritical fluid (SCF) media to effect recovery of previously dissolved pharmaceutical compounds. The quasi-instantaneous delivery of solutions alleviates the drawbacks of the use of capillary nozzles or micro-orifices, gradual elution and mixing controlled precipitation kinetics in existing SCF precipitation techniques. Most importantly, the energetic release of solution into SCF media effects supersaturation over a much larger spatial volume and promotes the homogeneous precipitation of low bulk density powders. ARISE processed insulin powders displayed characteristics that were highly influenced by anti-solvent conditions and powders of different qualities were obtained as a function of anti-solvent pressures. At lower anti-solvent pressures, powders of narrow particle size distribution were achieved, an indication of homogeneous supersaturation levels within processing. Span, the index of size distribution was as low as 0.991. At higher anti-solvent pressures, supersaturation rates were increased while mixing efficiencies decreased, resulting in powders of wider size distribution, and powder bulk densities as low as 0.01 g/ml. Low bulk density insulin displayed in-vitro respirable fractions as high as 78%.

Thesis (Ph. D.)--Rutgers University, 2007. / "Graduate Program in Chemistry and Chemical Biology." Includes bibliographical references.

Made available in DSpace on 2014-06-11T19:33:29Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-08-13Bitstream added on 2014-06-13T20:05:27Z : No. of bitstreams: 1 lima_ac_dr_arafcf.pdf: 901788 bytes, checksum: 13bcfcf5ec140760a159cf464fadf2e4 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Este estudo avalia as propriedades físico-químicas do praziquantel (PZQ) em dispersões sólidas (DS) preparadas através de tecnologia de fluido supercrítico (FSC). As DS de PZQ com polivinilpirrolidona K30 (PZQ: PVP K30) foram preparadas em condições supercríticas de temperatura e pressão que variaram de a 60 a 140 bars e 37 a 80ºC utilizando a técnica do Gás Antissolvente (GAS). Equilíbrio de solubilidade, perfil de dissolução, propriedades térmicas (DSC, TGA e TG), difração de raios X (DRX), infravermelho com transformada de Fourier (IV), microscopia eletrônica de varredura (MEV) e taxa de transporte, utilizando método do saco intestinal invertido, foram utilizados para caracterizar as DS em comparação com as misturas físicas (MF) e o PZQ. A solubilidade do PZQ nas DS aumentou significativamente com a diminuição da taxa PZQ: PVP K30. O estudo de dissolução mostrou aumento significativo da taxa de dissolução do PZQ nas DS. A DRX mostrou redução da cristalinidade do PZQ em todas as DS. O DSC e a TG mostraram que não houve alteração no ponto de fusão do PZQ e confirmaram o resultado da DRX em relação à redução da cristalinidade do PZQ. O DTA apresentou apenas uma temperatura de degradação revelando um composto organicamente puro e uma interação PZQ: PVP. O IV não mostrou nenhuma alteração significativa dos grupos funcionais do PZQ ou da PVP, o que sugere boa estabilidade para o composto. A MEV mostrou diferenças entre a interação física do PZQ com PVP K30 nas MF e DS. Estas interações foram evidenciadas no estudo de DRX. Um aumento significativo de cinco vezes na taxa de transporte do PZQ, através da membrana intestinal de ratos, foi observado para as DS. Os resultados obtidos confirmaram o potencial das DS para alterar propriedades físico-químicas importantes relacionadas à solubilidade do PZQ. A tecnologia de FSC utilizando o método GAS... / In this study, the physicochemical properties of praziquantel (PZQ) in solid dispersions (SD), prepared by supercritical fluid (SCF) methodology, were investigated. The SD of PZQ with polyvinylpyrrolidone K30 (PZQ: PVP K30) were prepared under supercritical conditions of pressure and temperature, ranging from 60 to 140 bars and 37 to 80 ºC, by the gas antisolvent process (GAS). Equilibrium solubility, dissolution profile, thermal properties (DSC, TGA and TG), powder X-ray diffraction (pXRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and gut transport rate, assessed in the everted gut-sac model, were used to characterize PZQ in SDs, in comparison with physical mixtures (PM) and PZQ alone. The solubility of PZQ in the SD increased significantly with decreasing PZQ: PVP K30 ratio. The rate of dissolution of the PZQ was significantly greater in the SD. The XRD patterns showed a reduction of the crystallinity of PZQ in all SD. DSC and TG showed that there was no change in the melting point of PZQ and confirmed the reduction in the crystallinity of PZQ detected by XRD. DTA showed only one degradation temperature, revealing an organically pure compound and a PZQ: PVP interaction. FTIR did not detect any significant changes in the functional groups of PZQ or PVP, suggesting that the compound has a good stability. SEM indicated differences between the PZQ-PVP physical interactions in the PM and SD. These interactions were evident in the XRD data. A significant 5-fold rise in the rate of transport of PZQ across the rat gut membrane was observed with the SDs. The results obtained confirmed the potential capacity of SDs to alter important physicochemical properties related to the solubility of PZQ. SCF technology, used in the GAS process, proved effective in the preparation of SDs of PZQ: PVP K30. These results and the insights gained in this study imply that... (Complete abstract click electronic access below)

Resumo: Este estudo avalia as propriedades físico-químicas do praziquantel (PZQ) em dispersões sólidas (DS) preparadas através de tecnologia de fluido supercrítico (FSC). As DS de PZQ com polivinilpirrolidona K30 (PZQ: PVP K30) foram preparadas em condições supercríticas de temperatura e pressão que variaram de a 60 a 140 bars e 37 a 80ºC utilizando a técnica do Gás Antissolvente (GAS). Equilíbrio de solubilidade, perfil de dissolução, propriedades térmicas (DSC, TGA e TG), difração de raios X (DRX), infravermelho com transformada de Fourier (IV), microscopia eletrônica de varredura (MEV) e taxa de transporte, utilizando método do saco intestinal invertido, foram utilizados para caracterizar as DS em comparação com as misturas físicas (MF) e o PZQ. A solubilidade do PZQ nas DS aumentou significativamente com a diminuição da taxa PZQ: PVP K30. O estudo de dissolução mostrou aumento significativo da taxa de dissolução do PZQ nas DS. A DRX mostrou redução da cristalinidade do PZQ em todas as DS. O DSC e a TG mostraram que não houve alteração no ponto de fusão do PZQ e confirmaram o resultado da DRX em relação à redução da cristalinidade do PZQ. O DTA apresentou apenas uma temperatura de degradação revelando um composto organicamente puro e uma interação PZQ: PVP. O IV não mostrou nenhuma alteração significativa dos grupos funcionais do PZQ ou da PVP, o que sugere boa estabilidade para o composto. A MEV mostrou diferenças entre a interação física do PZQ com PVP K30 nas MF e DS. Estas interações foram evidenciadas no estudo de DRX. Um aumento significativo de cinco vezes na taxa de transporte do PZQ, através da membrana intestinal de ratos, foi observado para as DS. Os resultados obtidos confirmaram o potencial das DS para alterar propriedades físico-químicas importantes relacionadas à solubilidade do PZQ. A tecnologia de FSC utilizando o método GAS... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: In this study, the physicochemical properties of praziquantel (PZQ) in solid dispersions (SD), prepared by supercritical fluid (SCF) methodology, were investigated. The SD of PZQ with polyvinylpyrrolidone K30 (PZQ: PVP K30) were prepared under supercritical conditions of pressure and temperature, ranging from 60 to 140 bars and 37 to 80 ºC, by the gas antisolvent process (GAS). Equilibrium solubility, dissolution profile, thermal properties (DSC, TGA and TG), powder X-ray diffraction (pXRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and gut transport rate, assessed in the everted gut-sac model, were used to characterize PZQ in SDs, in comparison with physical mixtures (PM) and PZQ alone. The solubility of PZQ in the SD increased significantly with decreasing PZQ: PVP K30 ratio. The rate of dissolution of the PZQ was significantly greater in the SD. The XRD patterns showed a reduction of the crystallinity of PZQ in all SD. DSC and TG showed that there was no change in the melting point of PZQ and confirmed the reduction in the crystallinity of PZQ detected by XRD. DTA showed only one degradation temperature, revealing an organically pure compound and a PZQ: PVP interaction. FTIR did not detect any significant changes in the functional groups of PZQ or PVP, suggesting that the compound has a good stability. SEM indicated differences between the PZQ-PVP physical interactions in the PM and SD. These interactions were evident in the XRD data. A significant 5-fold rise in the rate of transport of PZQ across the rat gut membrane was observed with the SDs. The results obtained confirmed the potential capacity of SDs to alter important physicochemical properties related to the solubility of PZQ. SCF technology, used in the GAS process, proved effective in the preparation of SDs of PZQ: PVP K30. These results and the insights gained in this study imply that... (Complete abstract click electronic access below) / Orientador: Maria Palmira Daflon Gremião / Coorientador: Marco Vinícius Chaud / Banca: Maria Palmira Daflon Gremião / Banca: Humberto Gomes Ferraz / Banca: Osvaldo de Freitas / Banca: Newton Andreo Filho / Banca: Mara Cristina Pinto / Doutor

Thesis (MTech (Chemistry))--Cape Peninsula University of Technology, 2017. / The continued use and popularity of plant-based traditional medicine demands scientific validation of the therapeutic potential of the medicinal plants used in disease management and treatment. These medicinal plants are to be evaluated for phytochemical constituents and pharmacologically screened for their bioactivity and include the isolation and identification of their bioactive compounds. The diabetes tea and its eight individual plants constituents were collected from Sing Fefur Herbs in McGregor, Western Cape. The plant material was ground to a fine powder form using a milling machine. The powdered plant material was sequentially extracted with hexane, 1:1 DCM, DCM:MeOH, MeOH and water. The antioxidant activity of the tea and its plants was evaluated with comparison to the antioxidant activity of brewed rooibos tea in literature. The concentration of antioxidants in the plants and the tea were found to be significantly high. The ORAC assay results of the water extracts were significantly higher than that of rooibos tea in all plants. Salvia africana-caerulea water extract ORAC results were 14147.10±1.02 μmol TE/g and this is 10 times better than the brewed rooibos tea results of 1402±44.1 μmol TE/g. The alpha-amylase enzyme inhibition assay showed no significant results while the alpha-glucosidase enzyme inhibition assays showed significant results in some of the extracts. The highest inhibitory activity towards alpha-glucosidase was found in the Urtica urens hexane extract and the Thymus vulgaris hexane extract (69.66% and 68.43%, respectively). This observation suggests that alpha-glucosidase enzyme is inhibited mostly by the less polar or medium polarity chemical components of the plant extracts. The crude plant extracts that showed significant activity in the antidiabetic bioassays were further subjected to cytotoxicity assay to ascertain the safety of extracts. The T. vulgaris DCM extract, Salvia officinalis DCM extract and Salvia officinalis hexane extract showed a cell growth inhibition of 54.91%, 62.14% and 63.87% at 100 μg/ml, respectively. The Salvia africana-caerulea DCM extract showed a cell growth inhibition of 59.10% at 50 μg/ml and 62.14% at 100 μg/ml. In the cytotoxicity analysis Salvia africana-caerulea DCM extract is the only extract that showed cell viability below 50% for both concentrations. Phytochemical screening of selected methanolic and aqueous extracts of the diabetes tea and the Salvia africana-caerulea showed the presence of alkaloids, sugars, flavonoids, glycosides, proteins & amino acids, phenolics & tannins and saponins. Furthermore isolation, purification and analysis of two Salvia africana-caerulea crude extracts (DCM and DCM:MeOH) were done in order to try and obtain pure compounds. The compound characterization was done through the use of chromatographic techniques. Thin layer chromatography (TLC), flash chromatography and column chromatography resulted in the generation of 29 fractions. Spectroscopic techniques utilized for chemical structural elucidation for compounds of interest included Liquid chromatography mass spectrometry and Nuclear Magnetic Resonance Spectroscopy. Of all the fractions generated, DM 23 was the purest and its structural elucidation was attempted.

A coerência do processo de fabricação, via granulação úmida, de comprimidos de dipirona sódica (500 mg) foi avaliada empregando ferramentas de qualidade e de estatística. No estudo foi desenvolvida base racional-científica objetivando determinar as etapas críticas do processo por meio da técnica de análise de modo e efeito da falha (FMEA). A análise de risco revelou as potenciais falhas do processo: variação da distribuição granulométrica da mistura final com elevado percentual de pó fino e problemas relativos a fluidez; ensaios de peso, espessura, dureza, friabilidade, tempo de desintegração e dissolução fora de especificação; não-uniformidade do conteúdo de dipirona sódica (OS) na mistura final e durante a compressão e ocorrência de laminação, capeamento, porosidade e aderência dos comprimidos às estações da máquina compressora. Os métodos analíticos relativos à determinação de (OS), empregando metodologia espectrofotométrica e de cromatografia líquida de alta eficiência (CLAE), foram previamente validados. As seguintes características de desempenho, em ambas metodologias analíticas, foram determinadas: especificidade, linearidade com coeficiente de correlação (r) > 0,99, repetibilidade aceitável com desvio padrão relativo (OPR) < 2% e precisão intermediária entre analistas e em dias diferentes. Além disso, a robustez e exatidão com percentual de recuperação entre 99,28% e 100,84% foram comprovadas para o método de CLAE. No que se refere às etapas críticas da validação do processo produtivo, foi elaborado plano de amostragem baseado nos critérios estabelecidos em compêndio oficial (FARMACOPÉIA BRASILEIRA, 1988), Guia da FOA (UNITEO STATES, 2003), duração de cada etapa de fabricação e tipo de equipamento utilizado. Além disso, foi empregada a lista Millitary Standard 105E (TAYLOR, ENTERPRISES, 1989). Os resultados relativos à estabilidade estatística do processo revelaram ausência de causas especiais. Os índices de capacidade Cp e Cpk foram calculados após avaliação da distribuição dos dados empregando teste de Anderson-Darling. Todos os dados apresentaram distribuição normal (p > 0,05), exceto àqueles relativos à uniformidade de conteúdo de OS na etapa de compressão. Esses dados foram tratados utilizando método proposto por Box-Cox (Iambda igual a 5) visando sua normalização. Os índices de capacidade Cp e Cpk. revelaram resultados > 1 e, portanto, permitiram determinar a consistência do processo e baixa probabilidade de falha. / The consistency of the metamizol tablets (500 mg) manufacturing process, via wetting granulation, was evaluated by quality and statistical tools. In this study, rational-scientific base was developed aiming determination of the critical steps of this process, using the Failure Mode and Effects Analysis (FMEA) technique. The risk analysis shows the potential failures of the process: variability of particle size distribution, high percentage of fine powder and flowability problems related to the final mixture; weight, thickness, hardness, friability, disintegration time and dissolution percentage of the tablets out-of-specifications; non-uniformity of the metamizol content in the final mixture and during the tabletting steps; laminating, capping, porosity and sticking of the tablets. The analytical methods performed by spectrophotometric and high performance liquid chromatography (HPLC), in order to assay metamizol, were previously validated. The following parameters were evaluated in both analytical methodologies: specificity, linearity with correlation coefficients more than 0.99, acceptable repeatability with relative standard deviation (RSD) less than 2% and intermediate precision between two different analysts and days. Besides that, the system suitability and accuracy were also proved by HPLC method. The recoveries obtained were between 99.28% and 100.84%. The sampling plan was elaborated according to official compendium (FARMACOPEIA BRASILEIRA, 1988), FOA Guidance (UNITED STATES, 2003), Military Standard 105E (TAYLOR ENTERPRISES, 1989), the duration of each step and the type of equipment used. This plan was just applied for critical steps identified by FMEA tool. The results related to the statistical stability of the process show no special cause. The capability indexes, Cp and Cpk, were calculated after the evaluation of the data distribution using Anderson-Darling test. Ali data showed normal distribution (p > 0.05), except for uniformity of metamizol content of the tablets. This data was treated by a method proposed by Box-Cox (Iambda equal -5.0) aimed at obtaining the normality of the data. The capability indexes, Cp and Cpk, obtained were all > 1. Therefore, this process can be considered consistent and with low probability of failures.

Foram produzidos comprimidos de liberação prolongada de teofilina baseados em matrizes hidrofílicas de misturas de hidroxipropilmetilcelulose e etilcelulose e polietilenoglicol. O planejamento estatístico de mistura Design Expert® foi empregado na seleção da composição do sistema de controle da liberação e, numa segunda fase, para otimização das formulações de comprimidos. Foram produzidas 26 formulações por compressão direta e as características físico-químicas dos comprimidos como peso médio, friabilidade, dureza e teor de fármaco foram determinadas. A porcentagem de teofilina liberada foi avaliada conforme o método da Farmacopéia Americana 30 ed. (2007), para cápsulas de liberação prolongada (Teste 10 - pá), por um período de 8 horas. Conforme as farmacopéicas os comprimidos produzidos apresentaram características físico-químicas de acordo com as especificações, com exceção das formulações 2 e 3, para o teste de friabilidade, cujos valores foram superiores. Entretanto, quanto ao ensaio de dissolução, a formulação 13, constituída por 30% de etilcelulose, atendeu aos valores preconizados para liberação prolongada de teofilina. As respostas obtidas dos experimentos foram introduzidas no programa Design Expert® que gerou superfícies de respostas nas quais foi possível avaliar a influência da composição nos parâmetros friabilidade e porcentagem de teofilina liberada na dissolução. Dessa forma, foi possível obter 3 formulações com etilcelulose (13,50% a 15,90%), metilcelulose tipo E4MCR (6,90% a 8,10%) e metilcelulose tipo K4MPRCR (0,30% a 0,60%), com as características desejadas empregando o planejamento estatístico de mistura, com o número mínimo de experimentos sem a necessidade de estudar todas as possíveis combinações experimentais, abreviando o trabalho com ganho de tempo. Os resultados encontrados para friabilidade e dissolução nas formulações otimizadas foram próximos dos previstos pela análise de regressão e dentro dos valores especificados na Farmacopéia Americana 30 ed. 2007. / Controlled release dosage forms of theophylline were prepared with hidrophyllic matrix using polymers as hydroxy-methyl-cellulose, hydroxy-ethyl-cellulose and polyethylenglycol. The program Design Expert® was used to select polymers composition and at the second moment, to optimized tablets formulations. It was obtained 26 formulations by direct compression that physical-chemical characteristics of tablets as weight deviation, friability, hardness and drug dosage were performed. Dissolution rate of these tablets were controlled by United States Pharmacopeia 30 ed. Test for theophylline extended-release capsules (test 10 - paddle) corresponding to 8 hours of experiment. The evaluation indicates that tablets produced were in accordance with Brazilian Pharmacopoeia 4 ed., and United States Pharmacopoeia 30 ed., except for formulations 2 and 3 that the values for friability were low. And about dissolution rate of these tablets only formulation 13 applied to preconized value for dissolution method for theophylline extendedrelease capsules. Design Expert® was fed with the results obtained from experiments that showed surface result after that it were possible to analyze the influence of the composition of components on the friability and dissolution rate of theophylline parameters. Considering the specifications, 3 formulations were obtained and were analyzed. The results obtained were close to results predicted for regression analysis and in accordance with Brazilian Pharmacopoeia 4 ed., and United States Pharmacopoeia 30 ed. The proposed experimental Design Expert® program strategy should allow a rapid evaluation and identification of the parameters important in determining the drug release rate from matrix tablets, providing a powerful support for their rational selection during preformulation studies and thus shortening the time necessary for the development of effective dosage forms with the desired drug release behavior.