Dissertations / Theses on the topic 'Ibuprofen'

A quitosana tem se mostrado muito atrativa para a indústria farmacêutica, visando principalmente matrizes de liberação controlada com fármacos amplamente utilizados pela população em altas dosagens ou em períodos prolongada tal como o Ibuprofeno. O uso de combinado de polímeros e materiais como a argila é uma opção interessante, unindo as propriedades de ambos os materiais, minimizando o efeito colateral do fármaco. No presente trabalho descreve-se a preparação de um complexo iônico contendo quitosana e ibuprofeno por meio de uma reação ácido base entre ambos. Em uma segunda etapa, foi preparado um nanocompósito de montmorilonita/quitosana contendo o fármaco ibuprofeno. As matrizes foram caracterizadas por diferentes técnicas, incluindo análise elementar, ressonância magnética nuclear (RMN) de 13C e 1H, termogravimetria (TG), calorimetria exploratória diferencial (DSC), difração de raios X (DRX) e espectroscopia de infravermelho com transformada de Fourrier (FTIR). O grau de desacetilação (GD) da quitosana obtido por titulação potenciométrica foi de 80,0%. Esses resultados foram confirmados por medidas de RMN 1H e RMN 13C. O estudo dissociação do fármaco, na presença e na ausência de argila, foi avaliado por cromatografia líquida de alta eficiência (CLAE) e por espectroscopia de absorção eletrônica UV-VIS. A dissociação do fármaco em meio aquoso foi avaliada em pH 2 e 7, que correspondem aos valores encontrados no estômago e no intestino, respectivamente. Os resultados indicaram que a dissociação do ibuprofeno das matrizes é dependente do pH e que a presença da argila retarda a dissociação do fármaco na matriz.
Due to its interesting properties chitosan has attracted interest regarding several applications including drug carrier in pharmaceutical industry, mainly for actives consumed in high doses for long periods, as Ibuprofen. The combined use of materials such as polymers and the clay is an interesting option, combining the properties of both materials while minimizing the side effects of the drug. A chitosan-ibuprofen ionic complex had been prepared from the acid-base reaction between both of them. In a second step a montmorilonite/chitosan nanocomposite containing ibuprofen was also prepared. The complex and the nacomposite containing ibuprofen had been characterized by several techniques including elemental analysis, 13C e 1H, nuclear magnetic resonance (NMR), thermogravimetry (TG), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and Fourrier transform infrared spectroscopy (FTIR). The chitosan degree of deacetylation (DD) was determined by potentiometry as 80.0%. These results were confirmed by 13C e 1H NMR. The dissociation of the pharmaceutical from the complex and nanocomposite was investigated by high performance liquid chromatography (HPLC) and electronic spectroscopy in the UV-vis (UV-vis). The dissociation of the pharmaceutical from the complex in aqueous media was evaluated in pH 2 and 7, corresponding to the stomach and intestines respectively. Results revealed that such dissociation is dependent of the pH of the medium as well as that release of Ibuprofen from the matrices is dependent on the pH and the presence of the clay slows the dissociation of the drug from the matrix.

O ibuprofeno é um anti-inflamatório não-esteroidal (AINE) que possui propriedades analgésicas e anti-térmicas e é empregado na terapêutica em casos dores discretas e moderadas, artrite reumatóide, osteoartrite e dismenorréia primária, nas concentrações de 200, 300, 400 e 600 mg. Entretanto, a formulação contendo 200 mg não está disponível no mercado farmacêutico brasileiro. No presente trabalho, foi desenvolvida uma formulação de comprimidos de ibuprofeno 200 mg que apresentou, além de outras características físico-químicas adequadas, um ótimo perfil de dissolução. Foram testadas oito formulações, obtidas a partir de um projeto fatorial fracionado, avaliando-se diversos excipientes. Além disto, as formulações foram submetidas à temperatura ambiente, 37 ºC e 50 ºC, e analisadas à 30 e 60 dias, com o objetivo de avaliar as transformações físicas que podem ocorrer durante o armazenamento das mesmas. Os resultados das análises físico-químicas foram tratados estatisticamente, utilizando-se o programa STATGRAFCS, através de uma análise exploratória e de um estudo de efeitos. Concluiu-se, então, que a melhor formulação foi a seguinte: IBUPROFENO - 200; AMIDO - 47; LACTOSE - 72; CELULOSE MICROCRISTALINA - 23; ESTEARATO DE MAGNESIO - 8.
Ibuprofen is a non steroidal antiinflamatory drug (NSAD), that has analgesic and antipyretic properties. It is used in terapeutic cases of mild to moderant pain, rheumatoid arthritis, osteoarthritis, and primary dysmenorrhea, in the 200, 300, 400, and 600 mg of concentration. In the Brazilian pharmaceutical market the formulation of 200 mg doesn\'t exist. In this study, a formulation of ibuprofen was developed for 200 mg tablets, that has suitable physical-chemical properties and an excellent dissolution profile. The eight formulations tested were obtained from factorial designs, evaluating several excipients. These formulations also had been submitted at room temperature, 37 ºC, and 50 ºC and were analised at 30 and 60 days, with the objective to evaluate the physical transformatiom that could have occurred during that time. The results were tested statistically by the STATGRAFCS program, using the exploratory analysis and the effects study. The final results showed that the best formulation was: IBUPROFEN - 200; STARCH - 47; LACTOSE - 72; MICROCRYSTALLINE CELLULOSE - 23; MAGNESIUM STEARATE - 8.

Orientadores: Lauro Tatsuo Kubota, Graciliano de Oliveira Neto
Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica
Made available in DSpace on 2018-08-08T00:59:06Z (GMT). No. of bitstreams: 1 Ribeiro_PauloJoseFernandes_M.pdf: 3526765 bytes, checksum: d7527897c70e194a6207d1020f2ce8bc (MD5) Previous issue date: 2006
Resumo: Nesse trabalho é apresentado o desenvolvimento de um eletrodo íon-seletivo para determinação de ibuprofeno, utilizando-se membrana do copolímero poli(etileno co-acetato de vinila) (EVA), tentando minimizar o uso de plastificantes. A membrana foi preparada diretamente sobre um suporte condutor constituído de uma mistura de resina epóxi, endurecedor e grafite. Na preparação da membrana foram estudadas diversas proporções de seus componentes, como concentração de par-iônico, influência do plastificante e quantidades de matriz polimérica. As melhores respostas foram obtidas com uma membrana composta de 115 mg do par-iônico aliquat-ibuprofeno, 170 mg de EVA e 150 mg do plastificante o-NPOE (orto-nitrofeniloctil-éter), não sendo possível eliminar o plastificante. Com o objetivo de otimizar as condições analíticas, foram feitos estudos da influência do pH, da natureza e concentração do tampão e de interferentes, além do tempo de reposta e de vida do eletrodo. As melhores respostas em estado estacionário foram obtidas em tampão Fosfato com concentração de 0,5 mol L a pH 7.0. Nestas condições foi verificado um bom desempenho do eletrodo na faixa de concentração de 2,93 10 a 10mol L, com limite de detecção de 8,7 10 mol L, sensibilidade de 127 mV década, tempo médio de resposta de 56 s e capacidade para aproximadamente 100 determinações. O eletrodo foi aplicado para determinação de ibuprofeno em amostras de medicamento obtendo bons resultados, sendo estes estatisticamente igual aos obtidos com o método de referência a um nível de 95% de confiança.
Abstract: In this work is presented the development of an ion-selective electrode for ibuprofen determination, using the poly(ethylene-co-vinyl-acetate) copolymer (EVA) membrane, trying to minimize the use of plasticizer. The membrane was prepared directly on a conducting support consisting of an epóxi resin, hardener and graphite mixture. In the preparation of the membrane several ratios of its components were investigated, such as concentration of ion-pair, influence of the plasticizer and polymeric matrix. The best performance was reached with a membrane composed with 115 mg of the ibuprofen-aliquat ion-pair, 170 mg of EVA and 150 mg of the o-NPOE (orto-nitrophenyloctyl-ether), being impossible to eliminate the plasticizer. Studies of the influence of pH, nature and concentration of the buffer and the interfering were carried out looking for the optimized conditions for the electrode performance like sensitivity, fast response and lifetime. The best response was obtained with Phosphate buffer in a concentration of 0,5 mol L at pH 7.0. In these conditions the electrode showed a good performance in the concentration range between 2,93 10 and 10 mol L, with a sensitivity of 127 mV/decade, a detection limit of 8,7 10 mol L, response time of 56 s and capacity for 100 determinations. The electrode was employed to determine ibuprofen in medicine samples obtaining good results, being statistically equal at 95% confidence level, when compared with the results obtained with the reference method for the same samples.
Mestrado
Quimica Analitica
Mestre em Química

Desde a década de 90 que estudos relacionados com os polímeros quitina e quitosana têm sido estimulados. A presença em maior quantidade de grupos NH2 na quitosana permite sua aplicação como biomaterial eficiente no carreamento de fármacos e na adsorção de cátions metálicos. Neste trabalho foram preparados filmes e microesferas de quitosana para uso em procedimentos de adsorção de íons prata, liberação de fármaco e atividade antibacteriana. O polímero apresentou grau de desacetilação correspondente a 81% e ponto de carga zero em pH~7. As microesferas obtidas apresentaram um diâmetro médio de 2,911 mm e um desvio padrão de 0,325, quando úmidas. O uso da quitosana na forma de microesferas e filmes proporciona um aumento da área superficial, além de facilitar o manuseio do polímero. Os filmes obtidos foram formados com nanopartículas de prata em etapa única. O melhor pH para o estudo de adsorção de íons Ag+ em meio aquoso está na faixa de pH de 5 a 7, o melhor ajuste foi ao modelo de Langmuir, o tempo ótimo para ocorrer adsorção máxima foi de 10 horas e o valor de energia aparente de adsorção (E) de 6,9 kJ/mol, o que a caracteriza adsorção física. O estudo de liberação de ibuprofeno foi realizado em fluido gástrico simulado e fluido intestinal simulado, a maior liberação do fármaco ocorreu no pH neutro dos fluidos intestinais. A liberação transdérmica de fármaco pelos filmes foi realizada apenas em pH=7,4 para simular o tecido sanguíneo e o ápice da liberação de ibuprofeno ocorreu logo no início do contato do material com o fluido simulado. As microesferas e os filmes com nanopartículas de prata demonstram ter atividade contra E. coli e S. aureus.
Since the 1990s studies related to chitin and chitosan polymers have been stimulated. The presence of more NH2 groups in chitosan allows its application as an efficient biomaterial without drug loading and adsorption of metallic cations. In this work, chitosan films and microspheres were made for use in silver ion adsorption procedures, drug release and antibacterial activity. The polymer showed a degree of deacetylation corresponding to 81% and zero loading point at pH ~ 7. As obtained microspheres had a mean diameter of 2911 mm and a standard deviation of 0.325, when used. The use of chitosan in the form of microspheres and films provides an increase of the surface area, besides facilitating the handling of the polymer. The films were formed with single step silver nanoparticles. The best pH for the Ag+ ion adsorption study in the aqueous medium is in the pH range of 5 to 7, the best fit for the Langmuir model, the optimal time for the maximum adsorption of 10 hours and the apparent energy value of adsorption (E) of 6,9 kJ / mol, which characterizes it physical adsorption. The study of ibuprofen release was performed in simulated gastric fluid and simulated intestinal fluid, further release of the drug occurs no neutral pH of intestinal fluids. Transdermal delivery of drug by films was performed at pH = 7.4 to simulate blood tissue and the apex of ibuprofen release occurred early in contact with the simulated fluid material. As microspheres and films with silver nanoparticles they demonstrate activity against E. coli and S. aureus.

Chromatography is widely used to determine physiochemical properties data including adsorption isotherm. In the separation of enantiomers through sorptive processes, supercritical fluids allow efficient and green alternatives to liquid solvent based systems. The isotherm information is vital in the development of operating policies and design of preparative chromatographic or moving bed separation schemes. Determination of sorption isotherms from experimental chromatographic elution data is automated and compared with different chromatogram model. Procedures were developed and validated for separation of R- and S- ibuprofen with supercritical 〖CO〗_2 and ethanol mixture as the mobile phase over a chiral stationary phase. The isotherms for the Langmuir, Freundlich, and Toth gave the similar results with a small residual for S-Ibuprofen at 150 bars and 40℃. Relative small amount of sample can be use from experiments to determine isotherms data that later be use for scale-up of the sorptive processes in industry to reduce time and cost.

Thesis (M.S.P.)--University of Toledo, 2004.
Typescript. "A thesis [submitted] as partial fulfillment of the requirements of the Master of Science degree in Pharmaceutical Sciences." Bibliography: leaves 94-112.

Thousands of tons of ibuprofen are produced and disposed of worldwide on an annual basis. Its impact on the environment is rarely studied; however some research has begun to demonstrate its negative impacts. Considering the amount consumed annually worldwide, it is crucial that alternative methods are found to treat waste water containing IBP and its metabolites. The objective of this project was to investigate the removal of ibuprofen in the presence of three oxidants; hydrogen peroxide, sodium persulfate and ozone. Furthermore, these oxidation experiments were carried out in the presence of three iron species; Fe 2+, Fe3O4 and Fe 2+ amended Fe3O4. First, magnetite (Fe3O4) was characterized using Brunauer Emmett Teller, X-Ray Diffraction, Transmission Electron Microscope and Scanning Electron Microscope. Furthermore, the adsorption isotherm and edge sorption were plotted and it was concluded that IBP has little affinity to Fe3O4 at the concentrations and pH at which the experiments took place. During the oxidative treatments almost no removal was observed for H2O2 and Na2S2O8 alone or in the presence of Fe3O4. By adding Fe2+ this removal increased to 95% and 63% respectively. In the case when only O3 was used, a removal of 28% was observed and the presence of Fe2+ hindered the oxidation of IBP (16% removal). Magnetite had shown very little or no effect during oxidation. Furthermore, second order rate constants were determined for H2O2 and Na2S2O8 in the presence of magnetite and for Na2S2O8 alone. The results showed that in the presence of magnetite the rate constant was slightly higher for H2O2 (k=3.0*10-3 M-1 s-1) than Na2S2O8 (k=1.59*10-3 M-1 s-1). Finally, several degradation products were detected by the different treatment methods; these include oxalic acid, 4-acetylbenzoic acid and oxo-ibuprofen. Based on these results it can be concluded that the best oxidative approaches amongst the ones studied were the use of hydrogen peroxide and persulfate activated by Fe2+. Therefore these should be considered as alternative methods to treat ibuprofen-containing wastes. These results also demonstrated the potential of using alternative oxides and magnetite for the treatment of pharmaceutical wastes.
Chaque année, des milliers de tonnes d'ibuprofène sont produites et donc potentiellement indirectement déversées dans l'environnement. L'impact environnemental de l'ibuprofène a été peu étudié mais quelques recherches ont démontré certains effets négatifs. Considérant la grande quantité consommée, il est essentiel d'identifier des méthodes de traitement efficaces pour les traitements d'eaux usées contenant de tels composés. L'objectif de cette thèse est d'étudier la dégradation de l'ibuprofène à l'aide de trois oxydants soient, le peroxyde d'hydrogène, le persulfate de sodium et l'ozone, et ce, en présence de trois espèces de fer soient, le Fe 2+, la Fe3O4 et la Fe3O4 rectifiée au Fe2+. Les méthodes de Brunauer Emmett Teller, diffractométrie de rayons X, microscopie électronique en transmission et microscopie électronique à balayage ont été employées pour caractériser la magnétite produite et utilisée lors des essais. De plus, l'isotherme de l'adsorption et le sorption en fonction de pH ont été déterminé. Ces résultats ont démontré que l'ibuprofène a une faible affinité envers la magnétite. Les résultats d'oxydation démontrent que le H2O2 et le Na2S2O8 sont de faibles oxydants mais, en présence du Fe2+, l'IBP est éliminé à 95% et 63%, respectivement. Dans le cas de l'O3, seulement 28% de l'IBP a été éliminé et la présence du Fe2+ a inhibé l'enlèvement de l'IBP (16% d'élimination). De plus, les constantes cinétiques ont été calculées en présence de la magnétite. La constante cinétique obtenu pour le H2O2 (k=3.0*10-3 M-1 s-1) est légèrement élevée que celle associée au Na2S2O8 (k=1.59*10-3 M-1 s-1). Finalement, les produits de transformation ont étudiés. Quelques-uns de ces produits ont été identifiés comme étant l'acide oxalique, l'acide 4-acetylbenzoique et l'oxo-ibuprofène. Cette étude démontre que les meilleures méthodes qui pourraient être considérées pour le traitement des eaux usées contenant l'ibuprofène sont le peroxyde d'hydrogène et le persulfate en présence de Fe2+. Ceux-ci démontrent également le potentiel des oxydes et de la magnétite pour le traitement d'eaux usées contenant des produits pharmaceutiques.

Thesis (M.S.)--University of Florida, 2006.
Typescript. Title from title page of source document. Document formatted into pages; contains 34 pages. Includes Vita. Includes bibliographical references.

Thesis (M.S.)--University of Florida, 2004.
Typescript. Title from title page of source document. Document formatted into pages; contains 31 pages. Includes Vita. Includes bibliographical references.

Pharmaceuticals are a group of emerging organic compounds of environmental concern used extensively in human and veterinary medicine. They are continually released into the environment as a result of manufacturing operations and excretion from humans and animals. These compounds enter directly into the municipal sewage systems and into wastewater treatment plants. A large number of important and potentially harmful organic contaminants, such as these pharmaceuticals, are not regulated in drinking and other waters. As a result, conventional technologies at most waste water treatment plants (WWTPs) discharge water that meet regulatory standards, yet are not specifically designed to remove these organic contaminants. Therefore, pharmaceutical compounds and their metabolites remain in discharged effluent and enter into the natural aquatic environment. Concentrations of pharmaceutical residues measured in water are typically reported in the ranges of ug/L to ng/L, which are at least three to four orders of magnitude lower than that required to produce a pharmacological effect. The probability of risks to humans arising from such an acute exposure is unlikely, but the possible effects resulting from life-long exposures and synergistic effects from exposure to many chemicals have yet to be determined. It has been widely reported that pharmaceuticals and their metabolites that enter into the aquatic environment can have a potential harmful effect on the aquatic ecosystem and can reach drinking water sources. This research focuses on non-steroid anti-inflammatory drugs (NSAIDs), a group of pharmaceuticals which are widely used as analgesic, antipyretic and anti-inflammatory agents. NSAIDs are frequently used because they are easily accessible as over the counter medication and are a group of drugs that do not produce addiction, respiratory depression, or drowsiness. There is an incentive for removing NSAIDs and other pharmaceuticals from the aquatic environment. Thus, quantitative evaluation of the fate of pharmaceuticals, proper risk assessment and improvement of the efficiency of WWTPs need sensitive and reliable analytical methods. The purpose of this project was to provide a method for detecting three common NSAIDs, IBF, KTF, and NAP, in purified water with LLE-GC-FID. And, an investigation of UV photolysis, UV/H2O2, and UV/TiO2 AOPs was performed to determine their effectiveness in treating IBF, KTF, and NAP in purified water. All treatment methods were successful in degrading target compounds with a total degradation of 86% or greater after 45 minutes. A liquid-liquid extraction technique using methylene chloride and BSTFA + 1%TMCS derivatizing agent was determined for detecting low concentrations of IBF, KTF, and NAP with calibration curves showing good linearity with all R2 values greater than 0.9880.

Orientador: Eduardo Dias de Andrade
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
Made available in DSpace on 2018-08-24T14:46:30Z (GMT). No. of bitstreams: 1 Mello_PaulaSampaiode_M.pdf: 885760 bytes, checksum: 88e6b3366a8005670f894bb45e4a4978 (MD5) Previous issue date: 2014
Resumo: Analgesia preemptiva é um regime analgésico instituído antes da lesão tecidual, porém sua eficácia na clínica endodôntica ainda é controversa. Este estudo avaliou se a dexametasona e o ibuprofeno promovem analgesia preemptiva em tratamentos ou retratamentos endodônticos, se comparados a um placebo, quando empregada a técnica de instrumentação do sistema de canais radiculares em que se trabalha 1 mm além do comprimento real do dente (ampliação foraminal). Para tal, 97 sujeitos foram divididos aleatoriamente em três grupos e tratados com dose única de 4 mg de dexametasona ou 600 mg de ibuprofeno ou placebo, via oral, 30 minutos antes da intervenção, de forma duplo cega. Ao fim do procedimento, os voluntários foram orientados a fazer uso de uma medicação analgésica de resgate (paracetamol 750 mg), somente em caso de dor. Foi anotado o período de tempo decorrido desde o final da intervenção até a tomada do primeiro comprimido de analgésico, além do consumo total desta medicação no período pós-operatório. A incidência e intensidade de dor foram avaliadas por meio de duas escalas analógicas, descritiva e numérica, preenchidas nos tempos de 4, 6 e 24 horas pós-operatórias. O período de tempo decorrido para a tomada do primeiro comprimido analgésico foi menor no grupo placebo (p<0,0001; teste de Kruskal-Wallis), enquanto que o consumo de comprimidos no período pós-operatório foi maior (p<0,0001; teste de Kruskal-Wallis). Com relação a estes mesmos parâmetros, não foram encontradas diferenças estatisticamente significantes entre os grupos tratados com a dexametasona ou ibuprofeno. Por sua vez, estes medicamentos promoveram uma redução significativa da dor pós-operatória nos tempos de 4 e 6 horas. Considerando a escala analógica descritiva, houve uma menor proporção de indivíduos com dor (leve e moderada) nos grupos tratados, em comparação ao grupo placebo. De acordo com a escala analógica numérica, também promoveram menores valores que o placebo. Não foi encontrada nenhuma diferença estatisticamente significante entre os três grupos após 24 horas, em nenhuma das duas escalas avaliadas. Conclui-se que a dexametasona e o ibuprofeno promovem analgesia preemptiva, reduzem a incidência de dor e a necessidade do uso de analgésicos após tratamentos e retratamentos endodônticos de elementos dentários assintomáticos, quando empregada a técnica de instrumentação do sistema de canais radiculares por meio de patência e ampliação dos forames apicais
Abstract: Preemptive analgesia is an analgesic regimen initiated before the onset of tissue trauma, however its efficacy on endodontic clinic is still controversial. This work evaluated whether dexamethasone and ibuprophen promote preemptive analgesia on endodontic treatments and retreatments, when compared to a placebo, when the radicular canals system instrumentation technique is employed, working 1mm beyond the real tooth length (foraminal enlargement). For this matter, 97 subjects were randomly divided into three groups and treated with a single dose of 4 mg of dexamethasone or 600 mg of ibuprofen or placebo, orally, 30 minutes before intervention, double-blinded. By the end of the procedure, volunteers were oriented to use a rescue analgesic medication (paracetamol 750 mg), only in case of pain. Notes were taken of the time period from the end of the intervention to the moment when the first pill was taken and also of the amount of medication taken during the post-operative period. The pain incidence and intensity were evaluated through two analog scales, descriptive and numerical, which were filled 4, 6 and 24 hours after the intervention. The time period until the first analgesic pill was taken was shorter for the placebo group (p<0,0001; Kruskal-Wallis test), while the consume of pills in the post-operative period was greater (p<0,0001; Kruskal-Wallis test). Considering these same parameters, no statistically significant differences were found among the groups that were treated with dexamethasone or ibuprofen. Nevertheless, these medications promoted a significant reduction of the post-operative pain after 4 and 6 hours. Considering the descriptive analogue scale, there has been a smaller proportion of patients with pain (either mild or moderate) in the groups that were treated, when comparing to the placebo group. According to the numerical analogue scale, they also promoted smaller values than the placebo. No statistically significant difference was found among the three groups after 24 hours, in any of the two evaluated scales. It may then be concluded that dexamethasone and ibuprofen promote preemptive analgesia, reduce the incidence of pain and the need of using analgesics after endodontic treatments and retreatments of the asymptomatic dental elements, when the radicular canal system instrumentation technique is employed through patency and enlargement of the apical foramens
Mestrado
Farmacologia, Anestesiologia e Terapeutica
Mestra em Odontologia

Orientador: Juliana Heloisa Pinê Américo-Pinheiro
Resumo: A qualidade da água é um assunto de crescente preocupação, especialmente devido à presença de fármacos que contaminam o ambiente aquático. Muitos compostos têm sido detectados em efluentes de estações de tratamento de esgoto (ETEs) e águas superficiais em todo o mundo. A ocorrência de fármacos no ambiente pode apresentar efeitos adversos aos ecossistemas aquáticos. O objetivo desse estudo foi avaliar a presença e a concentração dos fármacos diclofenaco, ibuprofeno e naproxeno durante março de 2017 a fevereiro de 2018 em 7 pontos de amostragem, sendo 5 pontos no Córrego das Marrecas - SP e 2 pontos na ETE do município de Dracena - SP. Em cada ponto do córrego foi mensurada a concentração de oxigênio dissolvido (OD), pH, temperatura e sólidos totais dissolvidos (SDT) com auxílio de uma Sonda Multiparamétrica Aquaread AP 2000. Para a identificação dos fármacos, as amostras foram preparadas por microextração líquido – líquido dispersiva e analisadas por cromatografia líquida de alta eficiência. Foi realizada uma análise descritiva para avaliação dos resultados de média, desvio padrão e coeficiente de variação dos parâmetros físico-químicos. Uma matriz de correlação foi aplicada para avaliar a interação entre os parâmetros físico-químicos da água e os fármacos dois a dois. Os três fármacos foram detectados em todos os pontos da ETE e do córrego. A maior concentração do diclofenaco (0,458 mg.L-1) foi registrada no ponto de lançamento do efluente da ETE no mês de março. Nesse ponto ... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Water quality is a subject of increasing concern, especially due to the presence of drugs that contaminate the aquatic environment. Many compounds have been detected in effluents from sewage treatment plants (ETEs) and surface water worldwide. The occurrence of drugs in the environment may have adverse effects on aquatic ecosystems. The objective of this study was to evaluate the presence and concentration of the drugs diclofenac, ibuprofen and naproxen during March 2017 to February 2018 in 7 sampling points, 5 points in the Stream of Marrecas - SP and 2 points in the TTE of the municipality of Dracena - SP The concentrations of dissolved oxygen (DO), pH, temperature and total dissolved solids (TDS) were measured at each point of the stream using an Aquaread AP 2000 Multiparameter Probe. For drug identification, the samples were prepared by dispersive liquid-liquid microextraction and analyzed by chromatography high efficiency liquid. A descriptive analysis was performed to evaluate the results of mean, standard deviation and coefficient of variation of physical-chemical parameters. A correlation matrix was applied to evaluate the interaction between the physicochemical parameters of water and drugs two to two. All three drugs were detected at all points of the TEE and the stream. The highest concentration of diclofenac (0.458 mg.L-1) was recorded at the point of launch of the ETE effluent in March. At that point, the highest concentration of ibuprofen (0.120 mg.L-1) was obse... (Complete abstract click electronic access below)
Mestre

Introdução: Devido ao fato dos antiinflamatórios serem amplamente utilizados no meio atlético, da suposta melhora de desempenho pelo efeito analgésico, independentemente da presença ou não de lesão, e, por fim, em razão dos extensos relatos de efeitos adversos associados a esta classe farmacológica, o objetivo da presente Tese Doutoral foi verificar a potencialidade do antiinflamatório não-esteroidal (AINE) Ibuprofeno em enquadrar-se como doping segundo o Código Mundial Antidoping da Agência Mundial Antidoping (WADA-COI), segundo critérios de ergogenia e risco à saúde em atleta em corrida de duração. Para tanto, foram realizados um estudo observacional e três ensaios clínicos, randomizados e duplo-cego. Materiais e Métodos: No primeiro trabalho (laboratorial), 14 atletas especialistas em provas de longa duração realizaram dois testes progressivos de corrida em esteira rolante com 72 horas de intervalo (modelo cruzado), sendo administrada em cada teste dose única e por via oral de 1,2g de AINE ou Placebo (lactose). Os resultados indicaram que o uso de AINE reduziu a percepção de esforço no segundo limiar ventilatório (p 0,01), todavia com diminuição da velocidade associada (p=0,01) e redução do VO2máx (p=0,04). No segundo estudo, 20 sujeitos (2x10 sujeitos) condicionados e saudáveis, após determinação da velocidade associada ao segundo limiar ventilatório, foram submetidos a um protocolo de tempo limite para exaustão (tlim) em corrida antes e 48h após indução de dano muscular com exercícios concêntricos e excêntricos (em dinamômetro isoscinético) nos grupos musculares do compartimento anterior e posterior da coxa. No segundo teste (pós-dano) um grupo recebeu, em dose única e por via oral, 1,2g de AINE e o outro grupo Placebo. Os resultados indicaram redução significativa do tlim em ambos os grupos (p 0,01), contudo sem atenuação de queda pelo AINE (p=0,55). No terceiro e último experimento, 14 atletas realizaram duas provas simuladas (PS) de 10 km em pista com sete dias de intervalo. Em cada dia os sujeitos receberam tratamento farmacológico idêntico aos estudos anteriores (modelo cruzado) tendo sido monitorados a filtragem glomerular (FG) pela técnica de clearance de 51CrEDTA, assim como o desempenho (tempo total de teste). Em ambas PSs foi observada redução significativa da FG (p 0,01), porém sem diferenciação entre as situações de uso de AINE e Placebo (p=0,235). O desempenho foi impactado negativamente pelo fármaco (p=0,02). Conclusões específicas: em corredores condicionados e atletas, a administração profilática de Ibuprofeno em dose única por via oral possui potencial chance de redução do desempenho por impactar possivelmente a distribuição volêmica ao tecido ativo (efeito associado à redução de hiperemia tecidual e à resposta cronotrópica frente ao exercício). Não restou assegurada sua eficácia analgésica sobre a atenuação do desconforto agudo (gerado pela corrida) ou tardio (gerado por dano prévio) no que tange a relação dor X desempenho. E por fim, a administração de dose única deste Ibuprofeno antes da corrida (nas condições de análise), não potencializa a condição de insuficiência renal aguda gerada pelo próprio exercício. Conclusão geral: O presente modelo experimental indica que o uso do antiinflamatório não-esteroidal Ibuprofeno não apresenta potencialidade de enquadrar-se como doping segundo Código Mundial Antidoping da WADA.
Introduction: Considering that anti-inflammatory drugs are widely used in the athletic community because of their supposed improvement of performance due to their analgesic action, either in the presence of lesion or not, and the numerous reports of the adverse effects associated with this pharmacological class, the aim of the present Doctoral Dissertation was to investigate the possibility of nonsteroidal anti-inflammatory ibuprofen being fit to be considered as doping according to the World Anti-Doping Code of the World Anti-Doping Agency (WADA-COI), by the criteria of ergogeny and risk to health in athletes in long duration run. To that purpose, three randomized, double blind clinical trials were performed. Materials and Methods: In the first trial (laboratory setting), 14 athletes experienced in long duration runs were submitted to 2 progressive tests of running on treadmill with a 72-hour interval between the tests (crossover design), with oral administration of a single dose of 1.2g NSAID or placebo (lactose) before each test. The results showed that the use of NSAID reduced the perceived exertion at the second ventilatory threshold (p 0.01), yet with decreased associated speed (p=0.01) and reduced VO2máx (p=0.04). In the second trial, 20 fit healthy subjects (2x10 subjects), after determination of the speed associated with the second ventilatory threshold, were submitted to a limit time protocol for exhaustion (tlim) in run before and 48h after inducing muscle damage with concentric and eccentric exercises (in isokinetic dynamometer) in the muscle groups of the anterior and posterior thigh compartment. In the second test (postdamage), one group was given a single oral dose of 1.2g NSAID and the other, placebo. The results showed a significant reduction in tlim in both groups (p 0.01), still without attenuation of fall by the NSAID (p=0.55). In the third and last test, 14 athletes performed two 10-km simulated runs (SRs) on track with a 7-day interval. On each day the runners received the same pharmacological treatment as in the previous trials (crossover design) and had their glomerular filtration rate (GFR) monitored by the 51CrEDTA clearance rate technique as well as their performance (total time of test). In both runs a significant reduction in the GFR (p 0.01) was observed, yet with no difference between the situations of using NSAID and placebo (p=0,235). Performance was negatively affected by the drug (p=0,02). Specific conclusions: In experienced, fit runners and athletes, prophylactic Ibuprofen administration in oral single dose is potentially able to reduce performance as it is likely to adversely affect volemic distribution to the active tissue (an effect associated with reduction in tissue hyperemia and chronotropic response resulting from exercise). Its analgesic efficacy on attenuating acute (caused by the run) or late (caused by previous damage) discomfort Is not guaranteed as the pain X performance relation is concerned. Finally, a single dose of Ibuprofen administered before the run (in the conditions investigated here) does not potentialize the acute renal failure condition caused by the exercise itself. General conclusion: The present experimental model indicates that the use of non-steroidal anti-inflammatory Ibuprofen cannot be considered as doping according to the World Anti-Doping Code of the WADA.

Submitted by Biblioteca da Faculdade de Farmácia (bff@ndc.uff.br) on 2017-03-14T17:58:37Z No. of bitstreams: 1 Feitosa, Lorena Rolim [Dissertação, 2015].pdf: 1298728 bytes, checksum: 4320200a78a4a14d77c8040a33f1d227 (MD5)
Made available in DSpace on 2017-03-14T17:58:37Z (GMT). No. of bitstreams: 1 Feitosa, Lorena Rolim [Dissertação, 2015].pdf: 1298728 bytes, checksum: 4320200a78a4a14d77c8040a33f1d227 (MD5)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Os sistemas autoemulsificantes são misturas da fase oleosa, tensoativos e co-tensoativos, que após diluição em meio aquoso, formam um sistema emulsionado, que por sua vez, é classificado como nanoestruturado caso formem partículas tão diminutas quanto às consideradas pertencentes a essa classe. Este sistema oferece uma alternativa viável e eficiente para veicular fármacos de baixa solubilidade, como o Ibuprofeno (IBF), melhorando sua performance de dissolução e, assim, seu desempenho biofarmacotécnico. O teste de dissolução é o método oficial de avaliação do comportamento in vitro de fármacos. Os ensaios in vitro são realizados no sentido de predizer o desempenho dos fármacos in vivo. O presente estudo objetivou desenvolver sistemas autoemulsificantes contendo altas doses de IBF incorporado em capsulas gelatinosas, bem como comparar o perfil de dissolução do sistema obtido com o do IBF em pó e com os produtos comerciais Motrin® e Advil® (cápsulas líquidas contendo 200 e 400 mg de IBF, respectivamente). Inicialmente, procedeu-se um estudo de solubilidade, para identificar as matérias primas potencialmente candidatas para comporem a formulação. A solubilidade do IBF nos diferentes meios foi determinada por metodologia analítica desenvolvida por espectrofotometria UV-Vis. Após a seleção das matérias-primas candidatas, obteve-se o diagrama pseudoternário, de modo a identificar as proporções entre fase oleosa e tensoativo/cotensoativo que gerem formulações autoemulsificantes, que em seguida foram submetidas ao teste de incorporação do IBF, com a adição do fármaco em concentrações crescentes (100, 200, 300 e 400mg). A distribuição de tamanho e o potencial zeta das partículas foram avaliados, respectivamente, pelas técnicas de espalhamentodinâmico da luz e mobilidade eletroforética. Duas formulações foram selecionadas, e preparadas com 200 e 400mg de IBF, nomeadas como 1C, contendo 50% do óleo (MOD®) e 50% dos tensoativos (Tween® 80 e Span® 80, sendo a proporção entre eles de 60,3% e 39,7%, respectivamente), de modo a atender o equilíbrio hidrófilo-lipófilo (EHL) requerido pelo óleo de 10,75, e 3C, contendo os mesmos componentes, adicionado o etanol como cossolvente a 10% na fase oleosa. Estas formulações foram avaliadas quanto ao teste de desintegração e de dissolução. A desintegração das cápsulas das formulações autoemulsificantes ocorreu em menor tempo do que os produtos comerciaisMotrin® e Advil®, o que contribui para uma potencial otimização do perfil de dissolução, no que diz respeito à velocidade de liberação a partir da forma farmacêutica. Os sistemas autoemulsificantes desenvolvidos apresentaram ainda perfil de liberação in vitrootimizado quando comparados ao fármaco puro em pó e às formulações comerciais Motrin® e Advil®, quanto aos parâmetros T50%, Q30min, e eficiência de dissolução (ED). Não foi possível descrever a cinética de liberação do fármaco a partir das formulações desenvolvidas com os modelos matemáticos estudados, pois a liberação de todo o conteúdo do fármaco ocorreu de forma imediata, sendo observada nos primeiros minutos do ensaio do perfil de dissolução. O tamanho médio de partícula das formulações desenvolvidas ficou entre 44 e 124nm, sendo classificadas como sistemas autonanoemulsificantes (SNEDDS), o que provavelmente justifica a otimização do perfil de dissolução alcançado com estas formulações. Observou-se ainda que, a inclusão do cossolvente etanol (10% da fase oleosa) à formulação proporcionou maior capacidade de solubilização do IBF.Estes resultados evidenciam o potencial do sistema autoemulsificante desenvolvido em veicular de maneira eficiente altas concentrações de IBF e otimizar o perfil de liberação do fármaco a partir desses sistemas, quando comparado ao IBF em pó e a produtos comerciais disponíveis no mercado
Self-emulsifying systems are mixtures of oil phase, surfactants and co-surfactants, that after dilution in aqueous media form an emulsified system, which is classified as nanostructured, if forms particle, so small as the ones classified in that category. This system offers an effective alternative to carry low-solubility drugs, such as Ibuprofen (IBF), improving its dissolution performance and thus thebiopharmacotechnical performance. The dissolution test is the official method of evaluation of the in vitro drug performance. In vitrotests are conducted in order to predict the drug performance in vivo. The present study aimed to develop self-emulsifying systems containing high doses of IBF incorporated into gelatin capsules and compare the dissolution profile of the obtained formulation with powder IBF and commercial products Motrin® and Advil® (liquid capsules containing 200 and 400 mg of IBF, respectively).Initially, it was performed a solubility study, to identify potential candidates vehicles to compose the formulation. IBF solubility in different media was determined by analytical methodology developed by UV-Vis spectrophotometry. After selecting the candidates vehicles, it was obtained a pseudo ternary diagram, in order to identify the proportions between oil phase and surfactants /co-surfactants, that generate self emulsifying formulations, which were then conducted to IBF incorporation test, with the addition of increasing drug concentrations (100, 200, 300 and 400mg).The size distribution and zeta potential of the particles were evaluated respectively by dynamic light scattering techniques and electrophoretic mobility. Two formulations were selected and prepared with 200 and 400 mg IBF, named as 1C, containing 50% of oil (MOD®) and 50% of surfactants (Tween® 80 and Span® 80, the ratio between them 60.3 % and 39.7%, respectively), to meet the hydrophile-lipophile balance (HLB) required by the Oil of 10.75, and 3C, containing the same components, included 10% of ethanol as co-solvent in the oil phase. These formulations were evaluated for disintegration and dissolution test. Disintegration of the capsules withself emulsifying formulations occurred in less time than commercial products Motrin® and Advil®, that contributes to a potential optimization of dissolution profile, concerning the speed release from the pharmaceutical form. The self-emulsifying systems developed additionally presented optimized release profile in vitro, when compared to the pure powder drug and commercial formulations Motrin and Advil®, for the parameters T50% Q30min and dissolution efficiency (ED). It was not possible to describe the drug release kinetics from the developed formulations with the mathematical models studied, as the release of the whole drug content immediately occurred, and was observed during the first minutes of the dissolution profile test. The average particle size of the developed formulations was between 44 and 124nm, thatis classified as self-nanoemulsifyingsystems (SNEDDS), which probably explains the optimization of the dissolution profile achieved with these formulations. It was also observed that the inclusion of co-solvent ethanol (10% of oil phase) to the formulation provided higher IBF solubilization capacity. These results demonstrate the potential of the developed self-emulsifying system for efficiently carryof high concentrations IBF and optimize the drug release profile from these systems, comparing with IBF powder and commercial products available in the market

Bisphenol A (BPA) is a compound that is commonly used in the manufacture of epoxy resins and plastics. Because of large scale production and widespread usages, BPA is released into the atmosphere through air, land, and water. BPA is weakly estrogenic in animals and has acute aquatic toxicity even at low concentrations of 1- 10μg/L. Ibuprofen is a widely used analgesic and antipyretic. Ibuprofen and its metabolites are mainly released into the environment by human urinary excretion. Ibuprofen has been detected at low concentrations in surface and waste waters. The environmental and health effects at such concentrations are unclear. The high removal of BPA and ibuprofen in the wastewater treatment plants (WWTPs), suggest that biodegradation might be responsible for the removal of these compounds. Several bacterial strains, isolated from waste water, are known to degrade BPA and ibuprofen. No studies, however, have reported using ammonia oxidizing bacteria for this purpose. Ammonia oxidizing bacteria (AOB) are an important group of microorganisms in nitrifying activated sludge of WWTPs. AOB are known to express ammonia monooxygenase (AMO) to degrade many different aromatic and aliphatic organics via cometobolic degradation (non beneficial mechanism). Nitrosomonas europaea is a widely studied AOB found to degrade synthetic estrogen by a study. This study aims to characterize the biodegradation of BPA and ibuprofen by AOB. The biodegradation ability of N.europaea with respect to BPA and ibuprofen was examined. Experiments were conducted in the presence/absence of the AMO inhibitor (allylthiourea), an external reducing energy source (sodium formate) and different primary substrate (ammonia) concentrations. The second part of the study comprises of biodegradation tests on BPA and ibuprofen using activated sludge from two WWTPs, one with one-sludge activated sludge system and the other one with two-sludge nitrification system. From the experiments conducted BPA at a concentration of 1.6 mg/L was degraded to 0.12 mg/L by N.europaea. BPA at concentrations of 1.0 mg/L and 0.75 mg/L was completely degraded by the cells. Resting cells of N.europaea were, however, unable to degrade BPA. Also ibuprofen of two concentrations, 0.42 mg/L and 0.8 mg/L, were not degraded by the culture. BPA at a concentration of 1 mg/L was degraded to 0.2 mg/L and ibuprofen at 0.5 mg/L was completely degraded by the activated sludge from the combined reactor. The activated sludge from the nitrification tank degraded BPA of concentration 1 mg/L and ibuprofen of concentration 0.5 mg/L completely. Hence, it can be summarized that Bisphenol A was degraded by N.europaea and also by the activated sludge obtained from the WWTPs. Ibuprofen was found incapable of inhibiting ammonia oxidizing bacteria in the case of the pure culture while it was successfully degraded by the mixed culture.

Ibuprofen is a non-steroidal anti-inflammatory drug with three major types of effect: anti-inflammatory, analgesic and antipyretic. Ibuprofen may be administered in a number of different forms via the oral as well as the topical route. Published evidence suggests that topical, unlike oral, non-steroidal anti-inflammatory drugs are associated with few systemic side effects as plasma concentrations are low compared to oral therapy. In some countries it is particularly difficult to obtain human skin for in vitro experimentation and it is therefore important to have alternate biological or synthetic membranes which mimic human skin for diffusion experiments. Synthetic membranes serve as predictive models for topical drug release and in South Africa, shed snake skin is easily obtainable from the many snake parks present in the country. The FDA guidelines were considered when choosing the apparatus to be used in the comparative diffusion study on proprietary ibuprofen-containing topical preparations from three countries and the verification of the usefulness, or otherwise, of shed snake skin as a biological membrane for the assessment of the permeation of ibuprofen. Two diffusion techniques were considered appropriate for the measurement of the amount of ibuprofen released from a topical formulation during in vitro testing. One was the Franz diffusion cell, as modified by Keshary and Chien (88,169) and the other was the European Pharmacopoeia diffusion cell (187). High performance liquid chromatography was used as the analytical technique for the analysis of ibuprofen in aqueous solution using ultraviolet detection at 222 nm. The validated method was applied to the determination of the diffusion of ibuprofen from topical ibuprofen-containing formulations (gels, creams and mousse) through synthetic silicone membrane and shed snake skin biological membrane from four different species. In a study of fifteen topical ibuprofen-containing formulations (gels, creams and mousse) from three countries (South Africa, United Kingdom and France) it was found that there was a trend of products from two countries consistently exhibiting superior diffusion characteristics as well as products from the same two countries consistently exhibiting the lowest diffusion of ibuprofen. Interpretation of the results of these studies demonstrated the importance of employing a combination of statistical analyses and peak integration values when drawing conclusions regarding comparative diffusion characteristics. Shed snake skin has been described as a 'model' membrane, i.e. a membrane which shows similar permeability to human stratum corneum. The results reported here show clearly that, for ibuprofen, the four species of snake produce shed skin with completely different diffusion characteristics when all other conditions are identical. It may well be that there is one particular species of snake which produces shed skin of identical permeability to human stratum corneum, but to describe shed snake skin in general as a model membrane seems incorrect. It is therefore important that if shed snake skin is used as a membrane, the species, skin site and orientation should be reported. The European Pharmacopoeia diffusion apparatus was judged to be the better of the two diffusion techniques assessed for the measurement of the amount of ibuprofen released from a topical formulation during in vitro testing using silicone membranes and for the measurement of the amount of ibuprofen diffusing across the ventral outside orientation of shed skin during in vitro testing, whereas the Franz diffusion apparatus was judged to be better for the measurement of the amount of ibuprofen diffusing across the dorsal outside orientation of shed skin during in vitro testing. However, the choice of this diffusion apparatus must be weighed against the relatively poor reproducibility as compared with the European Pharmacopoeia diffusion apparatus.

Halophytes are the main plant species of salt marshes, which are one of the most important habitats worldwide due to their ecological value and economic benefits. Pharmaceutical pollution has recently become one of the major human-induced threats to the natural environment. However, the effects of pharmaceutical pollution on plants are still unexplored. This research aimed to investigate the effect of Ibuprofen, one of the most common pharmaceuticals found in water bodies, on salt marshes plants. A negative effect of emergent pollutants like Ibuprofen on germination percentage or germination timing can potentially affect species population dynamics, and consequently, the integrity of salt marshes plant communities. To this aim, the best germination condition was selected for 4 halophyte species (Juncus acutus, Limonium vulgare, Sarcocornia fruticosa, Tripolium pannonicum). Then, seeds of the best germination species (Juncus acutus and Limonium vulgare) were sown in the Petri dishes at different concentrations of Ibuprofen (0, 2, 20, 200, and 2000 µg /l), and to combined solutions of NaCl + Ibuprofen. After 45 days of observation, to investigate seed ability to recover after salinity and Ibuprofen stress, recovery tests were carried out, by watering seed with fresh water only. Results showed that the best germination percentage, germination speed, and germination synchrony were in the control for both species J. acutus and L. vulgare. In J. acutus, Ibuprofen alone slightly decreased the germination percentage, speed, and synchrony, although not significantly. In L. vulgare, the pattern was less clear and less linear, showing non-significant effects at a concentration between (20 and 200 µg /l). Salinity significantly affected germination percentage, speed, and synchrony, both alone and in combination with Ibuprofen in both species. It completely inhibited the germination in J. acutus, while L. vulgare could germinate with low percentages (about 10 %). Nevertheless, recovery tests have shown that although with fluctuating patterns, seeds can recover from salinity, also when exposed to Ibuprofen. As a general pattern, we found that Ibuprofen had different effects on the two species, although they were non-significant for both species. It seems not to have interacted with salinity, while NaCl was a strong inhibitor of germination. This research for the first time empirically tested the effect of emergent pollutants such as Ibuprofen on the regeneration of wild species and provided important insight to understand plant dynamics, and their responses under new human- induced threats, such as contamination by emergent pollutants.

A pharmaceutical dosage form is an entity that is administered to patients so that they receive an effective dose of an active pharmaceutical ingredient (API). The proper design and formulation of a transdermal dosage form require a thorough understanding of the physiological factors affecting percutaneous penetration and physicochemical characteristics of the API, as well as that of the pharmaceutical exipients that are used during formulation. The API and pharmaceutical excipients must be compatible with one another to produce a formulation that is stable, efficacious, attractive, easy to administer, and safe (Mahato, 2007:11). Amongst others, the physicochemical properties indicate the suitability of the type of dosage form, as well as any potential problems associated with instability, poor permeation and the target site to be reached (Wells & Aulton, 2002:337). Therefore, when developing new or improved dosage forms, it is of utmost importance to evaluate the factors influencing design and formulation to provide the best possible dosage form and formulation for the API in question. Delivery of an API through the skin has long been a promising concept due to its large surface area, ease of access, vast exposure to the circulatory and lymphatic networks, and non-invasive nature of the therapy. This is true whether a local or systemic pharmacological effect is desired (Aukunuru et al., 2007:856). However, most APIs are administered orally as this route is considered to be the simplest, most convenient and safest route of API administration. Since ibuprofen is highly metabolised in the liver and gastrointestinal tract, oral administration thereof results in decreased bioavailability. Furthermore, it also causes gastric mucosal damage, bleeding and ulceration. Another obstacle associated with oral API delivery is that some APIs require continuous delivery which is difficult to achieve (Bouwstra et al., 2003:3). Therefore, there is significant interest to develop topical dosage forms for ibuprofen to avoid side effects associated with oral delivery and to provide relatively consistent API levels at the application site for prolonged periods (Rhee et al., 2003:14). The aim of this study was to determine the influence of selected formulation factors on the transdermal delivery of ibuprofen. In order to achieve this aim, the physicochemical properties of ibuprofen had to be evaluated. The aqueous solubility, pH-solubility profile, octanol-water partition coefficient (log P-value) and octanol-buffer distribution coefficient (log D-values, pH 5 and 7.4) of ibuprofen were determined. According to Naik et al., (2000:319) the ideal aqueous solubility of APIs for transdermal delivery should be more than 1 mg.ml-1. However, results showed that ibuprofen depicted an aqueous solubility of 0.096 mg.ml-1 ± 25.483, which indicated poor water solubility and would therefore be rendered less favourable for transdermal delivery if only considering the aqueous solubility. The pH-solubility profile depicted that ibuprofen was less soluble at low pH-values and more soluble at higher pH-values. Previous research indicated that the ideal log Pvalues for transdermal API permeation of non steroid anti-inflammatory drugs (NSAIDs) are between 2 and 3 (Swart et al., 2005:72). Results obtained during this study indicated a log P-value of 4.238 for ibuprofen. This value was not included in the ideal range, which is an indication that the lipophilic/hydrophilic properties are not ideal, and this might therefore; contribute to poor ibuprofen penetration through the skin. Furthermore, the obtained log D-values at pH 5 and 7.4 were 3.105 and 0.386, respectively. Therefore, it would be expected that ibuprofen incorporated into a formulation prepared at a pH of 5 would more readily permeate the skin compared to ibuprofen incorporated into a formulation prepared at a pH of 7.4. A gel, an emulgel and a Pheroid™ emulgel were formulated at pH 5 and 7.4, in order to examine which dosage form formulated at which pH would deliver enhanced transdermal delivery. Obtained diffusion results of the different semi-solid formulations were furthermore compared to a South African marketed commercial product (Nurofen® gel) in order to establish if a comparable formulation could be obtained. An artificial membrane was used to conduct the membrane permeation studies over a period of 6 h, in order to determine whether ibuprofen was in fact released from the formulations through the membrane. Skin permeation studies were conducted using Franz diffusion cells over a period of 12 h where samples were withdrawn at specified time intervals. All the formulations exhibited an increase in the average cumulative amount of ibuprofen released from the formulations and that permeated the membrane when compared to Nurofen® gel. This increase was statistically significant (p<0.05) for the gel, emulgel and Pheroid™ emulgel at pH 7.4. The gel at pH 7.4 exhibited the highest cumulative amount of ibuprofen that permeated the membrane. Preparations formulated at a pH of 5, did not differ significantly from Nurofen® when the average cumulative amount of ibuprofen that permeated the membrane were compared. The following rank order for the average cumulative amount released from the formulations could be established: Gel (pH 7.4) >>>> Pheroid™ emulgel (pH 7.4) > Emulgel (pH 7.4) >>> Gel (pH 5)> Pheroid™ emulgel (pH 5) ≈ Emulgel (pH 5) > Nurofen® gel. On the other hand, all the formulations exhibited an increase in the average cumulative amount of ibuprofen that permeated the skin when compared to Nurofen® gel. This increase was statistically significant (p < 0.05) for the gel, emulgel and Pheroid™ emulgel at pH 5, as well as the emulgel and Pheroid™ emulgel at pH 7.4. The emulgel at pH 5 exhibited the highest cumulative amount of ibuprofen that permeated the skin. The following rank order for the average cumulative amount released from the formulations and that permeated the skin could be established: Emulgel (pH 5) >> Pheroid™ emulgel (pH 5) > Gel (pH 5) > Emulgel (pH 7.4)> Pheroid™ emulgel (pH 7.4) ≈ Emulgel (pH 7.4) >> Nurofen® gel > Gel (pH 7.4). From this rank order it was clear that a trend was followed where the pH of formulation also played a role in ibuprofen permeation. All the formulations exhibited a higher release rate and flux when compared to Nurofen® gel. This was statistically significant for the emulgel, gel and Pheroid™ emulgel at pH 7.4. The gel at pH 7.4 exhibited the highest release rate and flux. This was observed for the membrane and skin permeation studies. All the formulations (including Nurofen® gel) presented a correlation coefficient (r2) of 0.972 – 0.995 for membrane permeation studies, and 0.950 – 0.978 for skin permeation studies; indicating that the release of ibuprofen from each of the formulations could be described by the Higuchi model. Furthermore, all the formulations exhibited a prolonged lag time compared to Nurofen® gel which indicated that the ibuprofen was retained for a longer time by the base. This was statistically significant (p < 0.05) for the emulgel at pH 7.4, the gel and Pheroid™ emulgel at pH 5. The gel at pH 7.4 exhibited a lag time closest to that of Nurofen® gel and this difference could not be classified as statistically significant (p > 0.286). This was observed for the membrane and skin permeation studies. Nurofen® gel exhibited the highest ibuprofen concentration in the stratum corneum as well as in the epidermis followed by the gel at pH 7.4. However, results obtained for all the formulations indicated that topical as well as transdermal delivery of ibuprofen was achieved. The pH of a formulation plays an important role with respect to API permeation. Ibuprofen is reported to have a pKa value 4.4 (Dollery, 1999:I1); and by application of the Henderson-Hasselbach equation, at pH 5, 20.08% of ibuprofen will be present in its unionised form and at pH 7.4, 0.1% ibuprofen will exist in its unionised form. Since the unionised form of APIs is more lipid soluble than the ionised form, unionised forms of APIs permeate more readily across the lipid membranes (Surber & Smith, 2000:27). Therefore, it would be expected that ibuprofen formulated at pH 5 would be more permeable than formulations at pH 7.4. However, this did not correspond to the results (membrane studies) obtained in this study. It may be attributed to the solubility of ibuprofen in the different formulations. According to the pH-solubility profile of ibuprofen obtained in this study, it was more soluble at pH 7.4 than at pH 5. This was due to the fact that ibuprofen is a weak acidic compound, and for every 3 units away from the pKa-value, the solubility changes 10-fold (Mahato, 2007:14). However, with regard to the skin permeation studies, enhanced permeation was obtained with the formulations prepared at pH 5. This was in accordance with Corrigan et al., (2003:148) who stated that NSAIDs are less soluble and more permeable at low pH values, and more soluble and less permeable at high pH values. This was most probably due to the fact that unionised species, although possessing a lower aqueous solubility than the ionised species, resulted in enhanced skin permeation due to being more lipid-soluble. Finally, stability tests on the different semi-solid formulations for a period of three months at different temperature and humidity conditions were conducted to determine product stability. The formulations were stored at 25 °C/60% RH (relative humidity), 30 °C/60% RH and 40 °C/75% RH. Stability tests included: mass variation, pH, zeta potential, droplet size, visual appearance, assay, and viscosity. No significant change was observed for mass variation, pH, zeta potential and droplet size over the three months for any of the different formulations stored at the different storage conditions. In addition, no significant change in colour was observed for the gel and emulgel formulations at pH 5 and 7.4 over the three months at all the storage conditions. However, it was observed that the formulations containing Pheroid™ showed a drastic change in colour at all the storage conditions. This might have been due to oxidation of certain components present in the Pheroid™ system. Consequently, further investigation is necessary to find the cause of the discolouration and a method to prevent it. The gel formulated at pH 5 depicted the formation of crystals. This might have been due to the fact that the solubility of ibuprofen was exceeded, leading to it precipitating from the formulation. A possible contributing factor to the varying assay values obtained during the study might have been due to non-homogenous sample withdrawal. On the other hand, no significant change was observed for the emulgel and Pheroid™ emulgel formulated at pH 5 and 7.4. The emulgel and Pheroid™ emulgel formulated at pH 5 depicted relative instability (according to the International Conference on Harmonisation of Technical Requirements For Registration of Pharmaceuticals for Human Use, ICH) only at 40 °C/75% RH with a change in ibuprofen content of more than 5% (6.78 and 6.46%, respectively). The gel, emulgel and Pheroid™ emulgel at pH 7.4 exhibited the least variation in ibuprofen concentration at all of the storage conditions. This might indicate that the pH at which a semi-solid formulation is produced will have a direct influence on the stability of the product. No significant changes in viscosity (%RSD < 5) was observed for the gel and emulgel formulated at pH 7.4 and stored at 25 °C/60% RH. The remaining formulations at all of the specified storage conditions exhibited a significant change in viscosity (%RSD > 5) with a decrease in viscosity being more pronounced at the higher temperature and humidity storage conditions. A possible contributing factor to the change in viscosity over three months at the specified storage conditions might have been due to the use of Pluronic® F-127 (viscosity enhancer). This viscosity enhancer possesses a melting point of approximately 56 °C (BAST Corporation. s.a). The problem with this might have been the temperature (70 °C) at which the formulations were prepared. The higher preparation temperature might have caused the Pluronic® F-127 to degrade, thereby losing its ability to function appropriately. A balance must be maintained between optimum solubility and maximum stability (Pefile & Smith, 1997:148). Despite the lower skin permeation of the gel formulated at pH 7.4, this formulation performed the best, as it was considered stable (least variation during the 3 month stability test) and the obtained tape stripping results showed that this formulation depicted the highest ibuprofen concentrations in the stratum corneum and epidermis. Thus, topical as well as transdermal delivery were obtained.
Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.
It is estimated over 20 million people aged 20‐74 have gallbladder disease, with biliary colic being a common and painful symptom in these patients. Likely due to the relatively recent approval of intravenous ibuprofen use for fever and pain in adults, no assessment of its analgesic efficacy for biliary colic currently exists in the literature. In this double‐blind, randomized, controlled trial we aim to assess the analgesic efficacy of intravenous (IV) ibuprofen given in the emergency department (ED) for the treatment of biliary colic. Analgesic efficacy was evaluated using a visual analog scale (VAS) to assess for a decrease in pain scores. A VAS score decrease of 33% in relation to the VAS taken at the time of therapy drug administration was considered a minimum clinically important difference (MCID) in patient‐perceived pain. A VAS was administered in triage upon enrollment, at the time of therapy administration, at 15‐minute intervals during the first hour post‐administration, and 30‐minute intervals in the second hour. As the standard of care for suspected biliary colic at the study institution is administration of a one‐time dose of IV morphine, patients were not denied initial morphine analgesia and were permitted to receive “rescue” morphine analgesia at any point during their ED course. A total of 22 patients completed the study. 9 were randomized to the IV ibuprofen arm, 9 to placebo, and 4 were excluded for a diagnosis other than biliary colic. Mean VAS values at time 0 to time 120 decreased from 5.78 to 2.31 in the ibuprofen group, and from 5.89 to 2.67 in the control group. There was no statistically significant difference in treatment status of ibuprofen vs. placebo (p‐value (p.) 0.93), though there was a significant decrease in the measured VAS scores over time (0 minutes to 120 minutes, p.0.031) in both ibuprofen and placebo groups. A statistically significant and clinically important decrease in average VAS scores were seen in both placebo and ibuprofen groups (55% and 60%, respectively). There was no difference in time needed to achieve a clinically significant reduction in pain between groups. The sample size of this study may be inadequate to fully assess the analgesic efficacy of IV ibuprofen for biliary colic. In the analysis group (n=18) no significant difference in treatment status of ibuprofen vs. placebo was seen, however there was a statistically and clinically significant decrease in pain in both groups. Two potential confounding factors may have affected the trial’s results: administration of standard‐of‐care IV morphine following initial triage assessment, and the inherent episodic and self‐limited nature of biliary colic.

Thesis (M Med(Otorhinolaryngology)) -- University of Limpopo, 2011.
Background: Tonsillectomy is one of the commonest operations performed by ENT surgeons. Pain, haemorrhage, delayed feeding and resumption of normal activities are common morbidities. Different groups of analgesics are used to reduce these morbidities. Objective: We examined the effectiveness of the use of three analgesics, some in combinations in reducing these morbidities. The primary outcome measures were pain, resumption of normal diet, resumption of normal physical activities and secondary haemorrhage. The secondary outcome was comparison of pain profile of children and adults. Methods: A prospective randomized double blind controlled study. Subjects were recruited and randomized into three study groups; group A (Paracetamol & Ibuprofen), group B (Ibuprofen) and group C (Paracetamol, Ibuprofen & Tilidine). A diathermy dissection technique was used on all patients in removing tonsils. Pain was measured using a patient morbidity scoring form (PMS) as well as the Smiley scale. The care givers for children and adult patients recorded all other events. Results: Sixty five patients were recruited, 30 were in group A, 20 in group B and 15 in group C. There were 36 females and 29 males. The youngest patient was 4 years of age and the oldest was 38 years. The mean number of days prior to resuming normal daily activities for groups A, B and C was 9.27, 10.60 and 7.67 respectively. Group C patients started their daily activities earlier than those in group B (p≤0.05). The average number of days to stop analgesic use was 12.3, 13.3 and 10.6 for groups A, B and C respectively. Patients in group C stopped using analgesics earlier than group B patients (p≤0.05). There was no statistically significant difference in PMS scores, resumption of normal diet, post-tonsillectomy haemorrhage as well as pain profiles of adults and children. Conclusion: Paracetamol-ibuprofen-tilidine combination appears to be more effective than either paracetamol-ibuprofen combination or ibuprofen in the first two weeks in the treatment of post tonsillectomy pain (p>0.05), however, further studies will have to be carried out to confirm this. Patients treated with a paracetamol-ibuprofen-tilidine combination appear to stop medication and return to their normal daily activities much earlier (p ≤ 0.05). Minor haemorrhage from the use of ibuprofen following tonsillectomy was not a cause for concern.

Objetivos: Avaliar o comportamento da pressão arterial (PA) e da frequência cardíaca (FC) durante a fase de dor da migrânea em pacientes sem hipertensão arterial sistêmica (HAS). Avaliar essas variáveis em função da intensidade de dor e se elas sofrem influência do uso agudo de ibuprofeno. Métodos: Dez pacientes (nove mulheres), entre 21 e 43 anos, com diagnóstico de migrânea foram selecionados. Todos tinham diagnóstico de migrânea sem aura e quatro deles também tinha diagnóstico de migrânea com aura. Eles apresentavam de 3 a 11 dias de dor por mês, não tinham qualquer outro problema de saúde e não estavam em tratamento profilático para migrânea. Além disso, não utilizavam medicamentos que pudessem interferir na PA ou FC. Os pacientes foram submetidos à anamnese e exame físico. Para descartar HAS, foram submetidos a medições convencionais da PA e Medidas Ambulatoriais da Pressão Arterial por 24h. A aquisição das medidas de PA e FC nos períodos livres de dor (interictal) foram realizadas por meio de Medidas Residenciais da Pressão Arterial (MRPA) por quatro a cinco dias consecutivos, com a obtenção de seis medidas ao dia. Para a aquisição das medidas de PA e FC no período de dor da migrânea (ictal), os pacientes foram orientados a fazer MRPA a cada 10 minutos nas duas primeiras horas de dor e, após, a cada 15 minutos até o final da crise. Ainda, deveriam assinalar em um tipo de diário de cefaleia as características da dor a cada hora. Permitiu-se o uso de 400mg de ibuprofeno como tratamento de resgate após o final da segunda hora de dor. Para análise estatística, comparamos os valores de pressão arterial sistólica (PAS), pressão arterial diastólica (PAD), pressão arterial média (PAM) e FC realizadas no período interictal com as realizadas no período ictal. As variáveis obtidas durante a cefaleia foram comparadas em função da intensidade de dor e em função do uso de ibuprofeno. Resultados: As médias de PAS, PAD, PAM do período ictal foram significativamente menores que as do período interictal (p0,01). Comparando as médias dos valores de PAS, PAD, PAM e FC do período interictal com as do período ictal divididas por hora para as primeiras quatro horas de dor, observamos que houve uma redução progressiva dos valores de PAS, PAD e PAM durante todo esse período (p0,01). Quanto à FC, observamos que houve aumento de seus valores na primeira hora de dor (p0,02). Houve uma tendência de redução dos valores das médias de PAS, PAD e PAM nas dores de moderada e forte intensidade. Com relação ao ibuprofeno, não notamos diferenças nas variáveis. Conclusões: Durante a fase de dor da migrânea ocorre uma redução da PA desde a primeira hora de dor. Por outro lado, há um aumento dos valores da FC apenas na primeira hora de dor. Houve uma tendência de que os valores de PA reduzissem à medida que a dor progredisse de leve para moderada e forte intensidades. O uso de 400mg de ibuprofeno não promoveu alterações nas variáveis analisadas.
Objectives: To analyse the behavior of blood pressure (BP) and heart rate (HR) during migraine headache in patients without hypertension (HBP). To assess the values of BP and HR according to the intensity of pain, and to check if those variable are influenced by 400 mg of ibuprofen. Methods: Ten patients (nine women), 21 to 43 years-old, with migraine diagnosis were select. All of them had migraine without aura and four of them also had migraine with aura. They had from 3 to 11 days of headache a month, no other healthy problem, and werent on migraine prophylactic treatment. Also, they werent using other drugs that could interfere on BP and HR. Patients were submitted to anamnesis and physical examination. Hypertension was ruled out through office and ambulatory BP measurements for 24 hours. To obtain the values of pain-free period, BP and HR were measured through home measurements which were done from 4 to 5 consecutives days, 6 times a day. To obtain the values of migraine headache period, patients were asked to measure their BP and HR from the beginning to the end of the attack. During the first two hour of pain, they should do the measures each 10 minutes, and after that each 15 minutes until the end of the attack. During the last procedure, patients should write in a kind of headache diary their headache characteristics each hour. Using of 400 mg of ibuprofen was just allowed at the end of the second hour of pain. To statistical analysis, the values of systolic (SBP), diastolic DBP), mean (MBP) blood pressure and HR from pain-free period were compared with the values of these variables from headache period. The values of these variables from headache period were also compared according the intensity of pain and the intake of ibuprofen. Results: The mean values of SBP, DBP and MBP from headache period were statistically lower than those from pain-free period (p0,01). Comparing mean values of SBP, DBP, MBP and HR from pain-free period to means from the headache period, separated by hour, for the first 4 hours of pain, we verified there were a progressive reduction of SBP, DBP, MBP during this phase (p0,01). About the HR, we noticed its values raised during the first hour of pain (p0,02). There was a trend of SBP, DBP and MBP values to be lower during moderate and severe pain. Regarding the use of ibuprofen, we didnt notice differences on BP or HR values. Conclusions: During migraine headache, BP values are lower since the first hour of pain. On the other hand, HR values were different just in the first hour of pain where they were higher. There was a trend of BP lowering as the pain progressed from mild to moderate and severe intensity. Ibuprofen (400 mg) didn\'t change the variables values.

Desde que en la década de los 90 se sintetizó el primer material mesoporoso ordenado se han estudiado diferentes rutas de síntesis con el objetivo de poder obtener materiales con los tamaños de poro y estructuras deseadas. En esta tesis se estudia la influencia de las variables de preparación y de composición sobre las propiedades de los materiales obtenidos a partir de cuatro tensioactivos diferentes. Las diferentes rutas de síntesis son estudiadas para evaluar las dificultades de implantación de estos procesos a nivel industrial. Se estudia la posibilidad de recuperar y reutilizar el tensioactivo utilizado como plantilla para los mesoporos así como una nueva manera de obtener dichos materiales a partir del uso de resinas de intercambio iónico. El uso de las resinas ácidas permite no utilizar el catalizador ácido y evitar así una etapa intermedia en la síntesis que conlleva una recuperación de tensioactivo con un grado menor de impurezas. Los materiales meso-macroporosos se obtienen a partir de emulsiones altamente concentradas y las gotas de la emulsión proporcionan los macroporos mientras que el tensioactivo da lugar a los mesoporos ordenados. La influencia de las diferentes variables es estudiada. Los materiales obtenidos son evaluados como sistemas de liberación de fármacos. Para ello se estudia la adsorción de ibuprofeno en ellos, y la posterior liberación de la molécula en un fluido corporal simulado.
Since ordered mesoporous materials were successfully synthesized, several authors studied different synthesis routes in order to obtain the materials with desired pore size or structure type. In this work composition and preparation variables were studied in order to evaluate the influence they had in the materials characteristics. Different synthesis routes were studied to evaluate the problems for the industrial viability. The surfactant recovery and its reuse as a template for obtaining the ordered mesopores were studied. A new approach to the industrial viability was reached by using ion exchange resins as a proton source. This resin provides acidic media and no acid was needed during the process, so the washing step was no longer necessary. The surfactant recovered by this method was free of impurities. Meso-macroporous materials were obtained from highly concentrated emulsions, and the droplets of the emulsions corresponded to the macropores of the materials. Ordered mesopores surrounding the macropores were obtained from the template provided by the surfactant. Influence of composition variables was studied. Different routes were used in order to find the one which provided a better result. Obtained materials were checked as drug delivery systems. Ibuprofen adsorption was studied and its posterior release in a simulated body fluid.

Táto práca sa zameriava problematiku interakcie ibuprofénu s pôdnym systémom. Popísané sú jeho základné vlastnosti, správanie a faktory ovplyvňujúce toto správanie. Vo všeobecnosti najvplyvnejšími faktormi je prítomnosť pôdnej organickej hmoty v pôde a pH. Ibuprofén patrí do skupiny nesteroidných protizápalových liečiv. Patrí medzi ľahko dostupné a vysoko konzumované liečivá. Toto prispieva k jeho narastajúcemu transportu a kontaminácii životného prostredia. Jeho prítomnosť v životnom prostredí môže pôsobiť negatívne na živé organizmy. V experimentálnej časti bol preskúmaný vplyv pôdnej organickej hmoty a pH na sorpciu a desorpciu ibuprofénu. Použité boli tri pôdy získané z odlišných regiónov Českej republiky. V rámci procesu sorpcie a desorpcie boli použité koncentrácie v rozmedzí 1 až 10 mg/l. Vplyv pH na sorpciu a desorpciu bol preskúmaný použitím koncentrácie ibuprofénu 10 mg/l a Britton-Robinsonovho pufru s pH 3, 7 a 10. Detekcia ibuprofénu v jednotlivých vzorkách bola uskutočnená pomocou UV-VIS spektrometrie a kvapalinovej chromatografie s hmotnostne spektrometrickou detekciou.

L’objectif principal de ce travail était l’étude et l’optimisation du procédé de lyophilisation en milieu aqueux et organique de l’ibuprofène. Une étude comparative approfondie a été réalisée à différents stades de la fabrication de l’ibuprofène lyophilisé pour les deux formulations étudiées. Cette étude comparative a été menée sur l’étape de formulation, sur le procédé de lyophilisation (congélation, sublimation, désorption) et sur les propriétés finales du produit (humidité, réhydratabilité, aspect…). On a observé, que l’utilisation comme solvant du mélange eutectique A, correspondant à une composition de 20% en TBA + 80% en eau (% massique), permettait une forte augmentation de la solubilité de l’ibuprofène et conduisait pour les mêmes conditions opératoires (Tshelf et Pc), à une augmentation des cinétiques de séchage d’un facteur 1,8, par rapport aux résultats observés avec la formulation d’ibuprofène à base aqueuse. Par ailleurs, la détermination expérimentale des valeurs des pressions de vapeur à l’équilibre solide-vapeur et de l’enthalpie de sublimation a été effectuée par deux méthodes différentes : la méthode thermogravimétrique et la méthode statique. Ces déterminations nous ont permis de conclure que l’augmentation des cinétiques de sublimation résultait essentiellement des valeurs plus élevées de la pression de vapeur à l’équilibre solide-vapeur et d’une valeur plus faible de l’enthalpie de sublimation de l’eutectique A par rapport à la glace. Ces données thermodynamiques ont aussi été utilisées comme paramètres clefs pour la modélisation de l’étape de sublimation sous Comsol Multiphysics. In fine, l’optimisation des paramètres opératoires de l’étape de sublimation par la méthodologie du Design Space a conduit à un lyophilisat final d’ibuprofène formulé à base organique qui satisfait entièrement aux critères standard de qualités recherchés (couleur, aspect, résidus de solvants etc). Un développement industriel de la formulation à base de co-solvant organique apparait plus avantageux qu’avec la formulation à base aqueuse
The main objective of this work was the study and the optimization of the freeze-drying process of ibuprofen with aqueous and/or organic based formulations. A detailed comparative study was realized at different steps of the ibuprofen freeze-drying process for both types of investigated formulations. This comparative study was realized at the succesives stages of freezing, sublimation and desorption and also concerned some properties of the final freeze-dried product (humidity, rehydratability, aspect…). We observed that the use of eutectic A mixture, corresponding to 20 % TBA + 80 % water (mass %) as co-solvent, allowed a strong increase of the solubility of ibuprofen and for the same operating conditions (Tshelf and Pc), led to an increase of drying kinetics values by a factor 1.8 by comparison to aqueous based formulations of ibuprofen. Besides, the experimental determination of equilibrium solid-vapour pressure and of sublimation enthaly values was carried out by using two different methods: the thermogravimetic method and the static method.These determinations allowed to conclude that the increase of sublimation kinetics resulted essentially from the higher equilibrium solid-vapour pressure values and from the lower sublimation enthalpy value of eutectic A by camparison to pure ice values. Next, these thermodynamical data were used as key parameters in the modelling of the sublimation stage under Comsol Multiphysics. In fine, the overall optimization of the operating parameters of sublimation stage was achieved by using the Design Space aproach. It proved that the organic based formulation led to final freeze-died cakes which fulfilled largely the main quality criteria (color, aspect, solvents residues, etc.). Thus, the development of an ibuprofen freeze-drying process with organic based formulation seems more advantageous than an aqueous based formulation process

The effect of crystallisation solvent on crystal morphology and mechanical properties of ibuprofen was studied. Intermolecular potentials were calculated to assess the relative growth rates of crystal faces of ibuprofen. Comparison of the predicted morphology with solution-"grown crystals clarified the interaction of solvent with the growing crystal. Single crystal dissolution and x--ray techniques indicated that crystals grown from non--polar solvents were more strained. In conjunction with solution NMR results (which showed differences in molecular association in solvents of varying polarity) this led to two different growth mechanisms being proposed. The crystal structure of resolved S(+) ibuprofen confirmed that enantiomeric dimers present in non-polar solvents could act as additives, selectively decreasing the growth rate at specific crystal faces, and introducing lattice strain. Deformation processes of ibuprofen did not appear to be changed by the solvent of crystallisation. However, crystals grown from non-polar solvents fractured readily. In conjunction with the unfavourable acicular morphology this is likely to be a source of processing problems of industrially produced crystals.

Mestrado em Ciência e Engenharia de Materiais
For the design of drug delivery systems, in which a large amount of drug should be stored and released over a sustained period of time, utilization of nanostructures is frequently advantageous as their high specific surface areas are beneficial for adsorptive drug loading. Additionally, the use of nanostructured drug carriers in concert with polymeric materials in composite drug delivery systems affords control over the drug release characteristics. While many combinations of materials can be imagined, the use of zinc-oxide and poly(urethane) is of particular interest in that nanostructures based on the former are easily producible and the latter is already an established material in biomedical applications. In this investigation, various aspects of the drug delivery properties were examined. In particular, the effects of altering the amount of drug loaded (by loading in solutions of 1, 2, 10, and 20 mg ibuprofen/mL ethanol) were studied and it was demonstrated that the amount of drug loaded can be controlled, which is important for customizing dosages in drug delivery systems. Additionally, the role of a washing procedure after loading the nanoparticles was examined in order to show that these procedures influence the drug loading by removal of loosely bound layers of drug. In completion of this study, the release of ibuprofen from both pure zinc oxide nanoparticles and the composites with poly(urethane) was investigated by tracking the concentration of drug present in a phosphate buffered saline solution containing the drug carrier with respect to time. In order better understand the mechanisms of drug release and analyze the degradation processes of the drug carrier, SEM images were produced for the samples at various times during the drug release process.
Para projectar um sistema de entrega de fármacos, em que se pretende armazenar uma grande quantidade de fármaco a ser libertada durante um período de tempo longo, é vantajoso recorrer a nanoestruturas com elevada área específica para o carregamento do fármaco por processos adsortivos. Além disso, a combinação de transportadores nanoestruturados com materiais poliméricos, formando sistemas compósitos para a entrega de fármacos pode proporcionar o controlo de certos parâmetros associados à libertação do fármaco. Entre as várias combinações possíveis, o óxido de zinco (ZnO) e o poliuretano (PU) oferecem um particular interesse dado ser possível preparar ZnO nanoestruturado e o PU ser um polímero com reconhecida aptidão para aplicações médicas. Neste trabalho, estudaram-se vários aspectos do processo de libertação de um fármaco modelo (o ibuprofeno) a partir de nanoestruturas de óxido de zinco e de compositos ZnO/PU. Em particular, estudaram-se os efeitos da variação da carga do fármaco usando soluções etanólicas com diferentes concentrações do fármaco,i.e. 1, 2, 10, e 20 mg de ibuprofeno / mL de etanol, tendo-se demonstrado que por esta via se pode controlar a carga do fármaco , o que é importante para personalização da dose em sistemas de entrega de fármacos. Além disso, a importância dos procedimentos de lavagem das nanoestruturas após carregamento do fármaco foi também avaliada, concluindo-se que tais procedimentos condicionam a carga de fármaco por remoção das camadas de fármaco fracamente adsorvidas. Estudou-se também a libertação de ibuprofeno a partir das nanoestruturas de óxido de zinco puro e dos compositos ZnO/PU, medindo a variação no tempo da quantidade de fármaco libertada em solução tampão de fosfato. Os perfis de libertação do fármaco aliados às imagens de microscopia electrónica (SEM) dos materiais obtidas no fim de diferentes períodos de tempo de libertação são usados neste trabalho para discutir os mecanismos de libertação do fármaco e avaliar a sua relação com a degradação do material em análise.

Mini-matrix multiple unit dosage forms (MUDFs) of diclofenac sodium and S(+) ibuprofen have been prepared. Normal tabletting techniques were used to form the mini-matrices prior to their enclosure in hard gelatin capsules. Four natural hydrophilic gums, namely xanthan, karaya, locust bean and carrageenan gums as well as hydroxypropyl methylcellulose (HPMC) were used as the principle release-retarding agents. Various excipients - lactose, Encompress®, cellulose acetate phthalate (CAP), Veegum F® and Avicel PH101® - were added in different proportions to further modify drug release. The diclofenac sodium mini-matrices (4.5 mm in diameter) were produced by the wet granulation method. The release profiles from several encapsulated minimatrices in phosphate buffer solution (pH 7.0) showed that xanthan, karaya and locust bean gums could sustain the release of diclofenac sodium while the carrageenan gum did not produce a satisfactory sustaining effect. The rank order of decreasing swelling rate in both axial and radial dimensions was xanthan > karaya > locust bean gum and each of these gums showed almost Fickian swelling behaviour. The solvent penetration rates were consistent with the swelling rates. However, the order of decreasing drug release and erosion rates was locust bean> xanthan > karaya gum. For each of these gums, the release behaviour was anomalous indicating that both Fickian drug diffusion and polymer relaxation were involved in the release process. The dominant mechanism depended on the nature and content of the gum, as well as the stage in the dissolution period. The study involving xanthan gum showed that the diclofenac sodium release rate declined linearly with a progressive increase in the gumcontent, without changing the release behaviour. However, for high drug: xanthan gum ratio (2:1), the release kinetics changed to Super Case II. Solubility differences between the excipients did not affect the release rate, but increasing proportions of each excipient produced a faster release rate with the release mechanism changing from anomalous to Case II and then to Super Case II transport. Mini-matrices containing HPMC produced faster drug release than those containing the three natural gums. There was no synergistic effect between xanthan and locust bean gums on the release of diclofenac sodium from mini-matrices. Variation in the stirring speed (used in the dissolution apparatus) and matrix volume had little effect on drug release, whereas the pH of the dissolution medium greatly affected the release of diclofenac sodium. Following on from the studies involving diclofenac sodium, xanthan and karaya gums were used to produce mini-matrices of S(+) ibuprofen. Excipients with good compressibility characteristics such as lactose, Encompress® and Avicel PH101® were needed in the formulations. At pH 7, higher drug release rates were obtained with karaya gum (Super Case II mechanism) compared with xanthan gum (anomalous behaviour). Solubility differences between the excipients slightly affected the release rate. Compression forces (11 - 26 kN) slightly affected the crushing strength. The minimatrices were relatively stable to variation in temperature (5 - 37°C) and relative humidity (10 - 75%) over a 2 month time period. These studies have shown that near zero-order release of diclofenac sodium and S(+) ibuprofen can be achieved using encapsulated mini-matrices formulations. The release mechanisms and release rates can be adjusted by variation of the type and content of gums and/or excipients.

Pharmaceutical Sciences
Ph.D.
It is a well reported fact that large number of drugs coming of the drug discovery pipeline show poor aqueous solubility. Eutectic mixture formation of poorly soluble drugs with hydrophilic carriers has been used to enhance the dissolution rate of such poorly soluble drugs. Eutectic mixtures are solid dispersions where the drug and the carrier are both in crystalline form. The eutectic mixture has a lower melting point than either component. Eutectic mixtures are thermodynamically stable systems. The feasibility of developing a dosage form from an eutectic mixture depends on the phase diagram. Poloxamers are polyoxyethylene-polyoxypropylene-polyoxyethylene block polymers which have surfactant properties. Phase diagram construction and dissolution rate enhancement mechanism in crystalline poloxamer based eutectics has not been reported in pharmaceutical literature. This thesis involved the detailed study of poloxamer 188 (PL 188) based eutectic mixtures. Eutectic mixture formation between PL 188 and drugs with diverse physicochemical properties was proved. Accurate experimental phase diagrams were constructed using solid state characterization techniques and theoretical phase diagrams were predicted using Lacoulonche et al's model. The model was accurate in predicting the phase diagrams of most drugs. Discrepancies were observed in case of drugs showing hydrogen bonding interactions with PL 188. This was confirmed by a blue shift of the carbonyl band using fourier transform infra-red spectroscopy. A unique novel graphical method for estimating the accurate eutectic composition of PL 188 based eutectics with about 50 mg of drug was devised. PL 188 was effective in improving the dissolution rate of a poorly soluble drug ibuprofen in pH 1, 4.5 and 7.2. For the first time a detailed study establishing melting point depression due to eutectic formation as a reason for dissolution enhancement was described. Contrary to expectation it was realized that maximum dissolution rate enhancement takes place at drug ratios well above the eutectic composition. The utility of PL 188 as a eutectic mixture carrier was shown by comparing ketoprofen PL 188 eutectic mixtures with ketoprofen soluplus (glass solutions) and ketoprofen urea solid dispersions(amorphous precipitation in crystalline carrier). The ketoprofen PL 188 eutectic mixtures had better dissolution enhancing effect and physical stability.
Temple University--Theses

Ce travail porte sur la préparation, la caractérisation physico-chimique et l'évaluation biopharmaceutique de Microparticules Lipidiques Solides Composites (MLSC) innovantes assurant la gastrorétention et la libération progressive d'un principe actif modèle hydrophobe, l'ibuprofène. Une méthode d'émulsification à chaud est utilisée pour préparer ces MLSC, stabilisées par des nanoparticules de silice Aérosil® d'hydrophobie variée, selon le principe des « émulsions de Pickering », en remplacement de surfactifs organiques. Ces nanoparticules inorganiques se retrouvent en surface et dispersées au coeur des MLSC dans tous les cas. L'utilisation d'Aérosil® hydrophobe permet la formation de MLSC homogènes de plus de 100 µm de diamètre. Il est à noter que la présence de silice, en fonction de la charge en ibuprofène, a une influence certaine sur les cinétiques de libération du principe actif, que ce soit dans le PBS de pH 7.4 ou le milieu gastrique simulé de pH 1.2, principalement en modulant la taille des microparticules. Elle permet aussi de stabiliser sur une période de 6 mois les propriétés physico-chimiques et biopharmaceutiques des MLSC, d'améliorer leurs propriétés d'usage, comme l'écoulement, la résistance à l'écrasement et la flottaison dans un milieu gastrique simulé. Enfin, le recouvrement des MLSC par des polysaccharides assure la bioadhésion sur des membranes biologiques simulées à base de mucine en accélérant le plus souvent la libération de l'ibuprofène. Néanmoins, la stabilisation de MLSC avec des nanoparticules de silice dispersées au sein de matrices d'alginate gélifiées au CaCl2 avant lyophilisation constitue une nouvelle voie prometteuse pour la libération prolongée de principe actif hydrophobe dans l'estomac car ce polymère assure leur bioadhésion sur plus de 4h sans toutefois modifier le profil de libération de l'ibuprofène
The aim of this work consists in the preparation, physic-chemical characterization and biopharmaceutical evaluation of innovative Composite Solid Lipid Microparticles (CSLM), allowing gastroretention and extended-release of a model hydrophobic drug, ibuprofen. Hot Melt emulsification's method is used to prepare these CSLM, stabilized by Aerosil® nanoparticles of various hydrophobicity as “emulsion of Pickering” instead of using an organic surfactant. Nanoparticles of silica take place on surface and are dispersed into CSLM in all cases. Using hydrophobic Aerosil allow the preparation of homogeneous over 100µm size CSLM. Presence of silica depending on the charge of ibuprofen influences the ibuprofen kinetics of release in both PBS ph 7.4 and simulated gastric fluid pH 1.2 by modulating the size of microparticles. Silica nanoparticles are also able to stabilize on a period of over 6 months the physic-chemical and biopharmaceuticals properties of CSLM, to improve their use properties, as helping free-flowing, enhancing crushing strength, and floating of CSLM in simulated gastric fluid. Finally CSLM coating with polysaccharides allows their bioadhesion on mucine simulated biological membrane, with an increased ibuprofen kinetics of release in most of the cases. Nevertheless, silica nanoparticles stabilized CSLM dispersed in CaCl2 gelified alginate matrices before freeze drying represent a new promising way for the extended release of hydrophobic drugs in stomach because this polymer can promote their bioadhesion for more than 4h without any change in the kinetics of ibuprofen release

During the last four decades, there has been a significant improvement in the management of coronary artery disease (CAD). These improvements have been achieved through the following advances: use of angioplasty with a stent; and, the development of drug eluting stents (DES). However, the occurrence of in-stent stenosis (ISS) following these procedures results in failure rates of 5-25% depending on the procedure. DES inhibit the proliferation and migration of vascular smooth muscle cells (VSMCs), the main culprit of restenosis and ISS. Fully functional endothelial cells inhibit potential side effects of angioplasty such as thrombus formation and VSMC proliferation and migration. Many studies have suggested that damage to the EC layer and inflammation are important factors that underlie ISS. Inflating the balloon and deploying the stent injures the vessel wall and induces an acute inflammatory response. Thus, anti-inflammatory agents might offer a novel approach for overcoming ISS. Previous studies in our laboratory have shown that non-steroidal anti- inflammatory drugs (NSAIDs) inhibit the proliferation ofVSMCs when used in non-toxic concentrations. In this project, we have investigated the effects of specific NSAIDs on EC proliferation and migration as well as on VSMC migration and phenotype and we try to address the possible mechanisms of actions involved. Our in vitro data indicate that the concentrations of ibuprofen required to inhibit EC migration are higher than those required to inhibit VSMC migration. The effects of aspirin and ibuprofen on proliferation and migration ofVSMCs may be partially mediated via PPARy through the regulation of integrin expressions, as the pretreatment with synthetic antagonist for PP ARy (GW9662 (1 ~M)), or natural antagonist for PPARy (PGF2a(100nM)) partially rescue the inhibitory effects of aspirin and ibuprofen; whilst, COX may mediate the effects of ibuprofen on VSMC proliferation and migration, but not of aspirin, as the exogenous PGF2a (10nM) could rescue the inhibitory effect of ibuprofen. Aspirin and ibuprofen switch VSMC phenotype from a synthetic (pathological) one into a contractile (healthy) phenotype. An IV ibuprofen drug-eluting stent may provide a novel therapeutic strategy for inhibiting an inflammatory response that promotes VSMC differentiation and leads to inhibition of proliferation and migration ofVSMCs without limiting healing of the EC layer.

Transdermal drug delivery has the advantage over other routes of administration of avoiding the hepatic, first–pass metabolism that would result in better therapeutic efficacy, better patient medication compliance and reduced systemic side–effects (Kydoneieus & Berner, 1987:69). One disadvantage of this mode of drug delivery is the generally poor delivery of drugs through the skin. The intercellular lipid structure of the stratum corneum causes this membrane to be an excellent penetration barrier, which must be breached to enhance drug penetration through the skin. Factors influencing the drug–skin distribution include the physicochemical properties of the drug, the choice of the delivery vehicle and the drug application mode (finite and infinite dose) being used (Chen et al., 2011:224). The permeability of the skin is thus influenced by the physicochemical properties of both the permeant and the penetration enhancer (Dias et al., 2007:65). One way of overcoming this barrier function of the skin is to include penetration enhancer chemicals in the topical application. Such penetration enhancers partition into the stratum corneum and interact with the intercellular lipids, causing a temporary and reversible decrease in this barrier function. With the skin barrier function being reduced, drug transport through the skin increases (Magnusson et al., 2001:206). When a drug or the penetration enhancer vehicle does not have the ideal physicochemical properties, penetration through the skin is difficult and manipulation of the drug or the vehicle is necessary. By manipulating their physicochemical properties, or by making use of penetration enhancers, the transdermal absorption through the skin can be increased (Park et al., 2000:109). Chemical penetration enhancers use different mechanisms of action to increase permeation across the skin (Moser et al., 2001:110). When chemical enhancers are used in combination, a synergistic action between these enhancers offers a method of overcoming limitations being experienced when single chemical enhancers are used in improving transdermal drug delivery (Williams & Barry, 2004:604). As mentioned, both the choice of vehicle and the physicochemical properties of the permeant and vehicle should be considered during drug skin distribution studies, as well as the mode of application (finite or infinite dose). When consumers use commercial formulations to treat topical skin conditions, the vehicles applied are in varying doses lower than 30 mg/cm2, depending on the application. In clinical situations, the formulation being applied depends on the body surface area being treated, i.e. the larger the surface area, the lower the amount of vehicle applied. When a cold sore is treated, for example, an average amount of 20 mg/cm2 of the vehicle is applied to the infected area, with the treated surface area generally being very small (Trottet et al., 2004:214). When sunscreens are applied to the skin, a very large surface area is treated and an average amount of only 0.5 mg/cm2 is applied (Azurdia et al., 1999:255; Bech & Wulf, 1992:242). It is thus clear that the transdermal absorption of an active compound depends on the concentration being applied and the surface area treated. Considering the above parameters is thus of high significance when in vitro transdermal diffusion tests are performed. Risk assessment studies comprise another important area in which clinical relevant dose plays a significant role when data on transdermal absorption of a substance is produced. During in vitro diffusion studies to determine the permeability profile of an active compound, an “infinite dose(s)” (> 150 ul) of the vehicle is applied to the membrane. One shortcoming of the infinite dose application is that in some instances it may fail to imitate the levels of active compound being applied to the skin when commercial formulations are applied. It may also fail to imitate exposure levels to toxic chemicals. Results from in vitro studies would differ from those obtained during in vivo studies, if the clinically applied concentrations are not taken into account. The aims of this study were to determine the penetration enhancement effects of different penetration enhancer vehicles on the permeation of lipophilic ibuprofen through synthetic Carbosil® membrane, when used individually and in multi–component solvent mixtures, as well as to determine the effects of finite (< 150 ul) dose applications of these enhancers on the delivery of ibuprofen. In order to achieve the aims of this study, the objectives were to determine the permeation of lipophilic ibuprofen through Carbosil® membrane by using: u Water and propylene glycol as penetration enhancer vehicles in combinations of 0/100 (v/v), 20/80 (v/v), 50/50 (v/v), 80/20 (v/v) and 100/0 (v/v); Mineral oil and Miglyol® as penetration enhancer vehicles in combinations of 0/100 (v/v), 20/80 (v/v), 50/50 (v/v), 80/20 (v/v) and 100/0 (v/v); and ; These penetration enhancer vehicles individually and in multi–component mixtures at different finite and infinite volumes, i.e. 2 ul, 5 ul, 10 ul, 20 ul, 50 ul, 150 ul, 250 ul, 500 ul and 1,000 ul; and to determine Which of the single or multi–component penetration enhancer vehicles would show the best transdermal delivery enhancement effect. The solvents used all have different mechanisms of action by which they enhance penetration of drugs through skin. By using these solvents in combination, the expectation was that they would have a synergistic effect that would be higher than the penetration enhancement effect achieved with each individual solvent (Williams & Barry, 2004:604). The outcomes of this study were as follows: The results for infinite dose applications of water and propylene glycol clearly showed that the best penetration enhancement of ibuprofen was achieved with 100% propylene glycol as the delivery vehicle. Contrary, water showed very little penetration enhancement properties for this drug. Results from this study also showed that the penetration enhancement effect of propylene glycol increased as the percentage of the propylene glycol in the solvent vehicle increase. This could have been as a result of the mechanism of action of propylene glycol to partition into the membrane and to increase the solubility of the permeant in and diffusion through the membrane (Squillante et al., 1998:266). Chen et al. (2011:224) suggest that the higher the applied volume, the larger the surface area being covered by the vehicle and the thicker the layer of the vehicle solvent on the surface of the membrane, which would result in an increase in the hydration of the membrane, which in turn would increase the permeability of the membrane for the drug. Application of finite doses of the single penetration enhancer solvent, propylene glycol, achieved the highest penetration enhancement effect, with the ibuprofen concentration of diffused ibuprofen being the highest with this solvent. The concentration of diffused ibuprofen that had been delivered from application of a finite dose of the water delivery vehicle could not be measured, due to the lipophilic nature of ibuprofen (log Po/w of 3.6) (Beetge et al., 2000:164) and the low solubility of ibuprofen in water, resulting in permeation concentrations that were immeasurable. Results for the infinite dose applications of the lipophilic, single phase solvents of 100% mineral oil and 100% Miglyol®, showed the lowest penetration enhancement effects, compared to all multi–component combinations of these two enhancer vehicles. Multi–component mixtures of these solvents also showed very similar permeation profiles for ibuprofen. This could have been as a result of synergistic action between the two penetration enhancer solvents if used in combination. According to Moser et al. (2001:106), Miglyol® is known to modify the intercellular lipids of the stratum corneum, causing disruption of the barrier properties thereof and hence an increase in diffusivity through the membrane. Since Carbosil® membrane and human epidermis share a common solubility–diffusion mechanism of drug transport, it can be hypothesised that the Miglyol® would change the polar structure of the membrane and as a result enhance the permeability of substances through the membrane. Mineral oil is a lipophilic solvent and while Miglyol® modifies the heteropolar structure of the membrane to make it more viable to penetration, mineral oil would carry the active to the lipophilic section of the membrane and as a result enhance the permeation of the lipophilic drug, ibuprofen (Hori et al., 1991:33). Results for finite dose applications of these solvents clearly showed that the 20/80 (v/v) mineral oil/Miglyol® combination achieved the best penetration enhancement effect for ibuprofen, compared to all other mineral oil and Miglyol® solvents, individually and in combination. Solvents and solvent mixtures containing 100% Miglyol®, 50/50 (v/v) and 80/20 (v/v) mineral oil/Miglyol® all showed similar penetration enhancement effects with finite dose applications. With solvent type permeant preparations applied to a membrane, three types of penetration influencing parameters should be taken into account, i.e. (a) thermodynamic effects resulting from different permeant solubilities in the different vehicles, (b) penetration enhancing effects between the vehicle and the membrane, (c) permeant depletion in the vehicle in the case of finite dose conditions. The extent of permeant depletion in the vehicle depends on the thickness of the applied solvent layer on the surface of the membrane (Leopold, 1998:167). The results from this study confirmed the observations by Williams and Barry (2004:605) that: 1. Penetration enhancer properties appear to be drug specific (permeants with similar physico–chemical properties). 2. Penetration enhancers tend to work well with co–solvents, such as propylene glycol. 3. Most penetration enhancers have a complex concentration dependent effect. 4. Potential mechanisms of action of penetration enhancer solvents are different and can range from direct effects on the skin to modification of the formulation. The outcomes of this study showed that increased levels of a penetration enhancer solvent, like propylene glycol in the delivery vehicle, not only increases the penetration of the active through the membrane, but it also improves penetration of the active through the membrane from finite dose applications. The permeation profiles of the lipophilic, single phase mineral oil and Miglyol®, and combinations thereof, showed that permeation of the lipophilic ibuprofen was higher with small application volumes of these delivery vehicles. Chen et al. (2011:224) report that with an infinite dose application, the donor compartment is filled with a thick liquid layer covering the surface of the membrane, having a height of 1.6 mm, while the finite dose application forms only a thin layer of 0.1 mm. As a result, the hydration levels of the membrane are higher with infinite dose applications, which facilitate higher permeability of the membrane (Chen et al., 2011:224). Increased membrane hydration appears to increase the diffusion of both hydrophilic and low lipophilic compounds, due to the partitioning of the active into the membrane (Williams & Barry, 2004:605). This hydration effect on the membrane makes penetration of hydrophilic mpounds through the membrane easier, whilst making it more difficult for strongly lipophilic compounds (log P >2) to partition into the hydrated membrane (Zhang et al., 2010:895). Ibuprofen is a strongly lipophilic drug (log P = 3.6) (Beetge et al., 2000:164), hence the lower permeation results for infinite dose applications. Except for mineral oil that showed higher permeation levels with larger volumes, as a result of the lipophilic nature of both mineral oil and ibuprofen, the permeability of the lipophilic active increased as the membrane became more hydrated with the lipophilic solvent when larger volumes were applied. From the findings in this study it has become evident that: * The lipophilic/hydrophilic nature of the solvent and the permeant play a significant role in the absorption of a permeant through the membrane. This is an important factor in risk assessment studies, especially; * If the membrane is hydrated with a lipophilic delivery vehicle while carrying a lipophilic toxic permeant, the effect may be more harmful at lower levels of exposure; Lipophilic ibuprofen showed higher permeation levels with small application volumes of Miglyol® and of lipophilic mineral oil/Miglyol® combination delivery vehicles. * When a lipophilic toxic permeant comes in contact with a hydrophilic delivery vehicle, like propylene glycol and water, the effect may not be as significant even with high levels of exposure; and * The nature of the delivery vehicle and the permeant, as well as the level of exposure or application, play enormous roles in the prediction of permeant absorption through Carbosil® membrane or the skin.
Thesis (PhD (Pharmaceutics))--North-West University, Potchefstroom Campus, 2012.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most abundant environmental pharmaceutical contaminants. In this study, a proteomic analysis was conducted to identify proteins differentially expressed in gill tissue of zebrafish (Danio rerio) after a 14-day exposure to the NSAIDs ibuprofen or naproxen. A total of 104 proteins with altered expression as indicated by 2-dimensional electrophoresis were analyzed by liquid chromatography with ion trap mass spectrometry (MS/MS). A total of 14 proteins fulfilled our requirements for identification which included consistency among replicate gels as well as successful MS/MS ion searches with the MASCOT database. The most prominent feature of the differential protein expression observed after NSAID exposure was an up-regulation of proteins belonging to the globin family which are involved in the transport of oxygen from gills and availability of heme molecules required for synthesis of cyclooxygenase. Differential expression was observed at exposure concentrations as low as 1-10 µg/L indicating that altered gene expression may occur in fish subjected to environmentally realistic levels of NSAID exposure.