Objetivos: Avaliar a farmacocinética do éster etílico de indometacina (IndOEt) em ratos Wistar, após sua administração oral (p.o) e intravenosa (i.v.) nas formas livre ou nanoencapsulada, e monitorar a formação de indometacina (IndOH) in vivo. Metodologia: Os protocolos experimentais foram aprovados pelo Comitê de Ética em Pesquisa da UFRGS (2005478). Nanocápsulas (NC) contendo IndOEt (IndOEt- NC) foram administradas p.o. (10 mg/kg) e i.v. bolus (5 mg/kg) a ratos machos Wistar (n = 5 a 7/grupo) e as concentrações plasmáticas de IndOEt e IndOH resultantes foram determinadas por CLAE com detecção por UV, empregando-se metodologia validada. Os grupos controle foram tratados com suspensão aquosa de IndOEt (10 mg/kg), com ou sem polissorbato 80, ou com IndOH pelas vias i.v. ou p.o. (10 mg/kg) (n = 7 a 11/grupo). Os perfis plasmáticos individuais foram avaliados por abordagem não-compartimental e compartimental utilizando os softwares Excel® 2003 e Scientist® 2.01, respectivamente, para a determinação dos parâmetros farmacocinéticos, que foram comparados estatisticamente utilizando-se teste “t” de Student ou ANOVA (α = 0,05). A avaliação do local de absorção p.o. de IndOEt-NC foi realizada pela quantificação de IndOEt e IndOH no plasma periférico e da veia porta, homogeneizado de fígado e de parede, bem como conteúdo, de porções do intestino delgado (n= 4/tempo) após a administração oral da formulação. Resultados e Discussão: Após a administração de IndOEt-NC por ambas as vias, apenas a IndOH foi detectada, indicando uma rápida hidrólise do éster. Em todos os casos, o IndOEt não alterou os parâmetros farmacocinéticos da IndOH, exceto a biodisponibilidade. Os perfis plasmáticos de IndOH i.v. foram descritos pelo modelo de 2 compartimentos, e os orais, pelo de 1 compartimento com absorção de primeira ordem. A avaliação da absorção oral de IndOEt-NC evidenciou que o IndOEt é, provavelmente, liberado e hidrolisado ainda na luz do trato gastrintestinal, sendo a IndOH formada in vivo e absorvida. Conclusões: O IndOEt nanoencapsulado ou não, quando administrado pelas vias oral e i.v., é rapidamente convertido a IndOH. A IndOH é, portanto, responsável pela atividade antiedematogênica relatada para o IndOEt-NC. / Objective: To evaluate the pharmacokinetics of either nanoencapsulated (NC) or free indomethacin ethyl ester (IndOEt) after intravenous (i.v.) and oral (p.o.) administration to Wistar rats and to determine the pharmacokinetics of indomethacin (IndOH) formation. Methodology: Animal experiments were approved by UFRGS Ethics in Research Committee (# 2005478). The pharmacokinetics was investigated in male Wistar rats after oral and i.v. administration of IndOEt-NC (10 mg/kg and 5 mg/kg, respectively) (n = 5-7/group) and IndOEt and IndOH plasma concentrations were determined by a validated HPLC with UV detection method. The control groups were treated with IndOEt aqueous suspension (10 mg/kg p.o.) or with IndOH aqueous suspension by the p.o. or i.v. routes (10 mg/kg) (n = 7 -11/group). Noncompartmental and compartmental approaches were used for individual profiles analysis using Excel® 2003 or Scientist® 2.01 softwares, respectively. The site of IndOEt-NC oral absorption was investigated in peripheral and portal vein plasma, hepatic tissue, intestine epithelia, and lumen content (n = 4/time). Results and Discussion: After IndOEt administration by both routes, only IndOH was detected in plasma, suggesting a fast hydrolysis of the ester. The IndOH parameters after administration of IndOEt and IndOH were similar, except for the bioavailability. The pharmacokinetic parameters of IndOH were modeled by two compartment open model after i.v. dosing and by one compartment with first order absorption after oral administration. After oral administration, IndOEt-NC was converted in IndOH in the gastrointestinal tract and then absorbed as such. Conclusions: After i.v. and oral administration, either IndOEt-NC or the free drug is quickly converted in IndOH. After oral administration, IndOEt-NC is released and hydrolyzed to IndOH following its absorption at the gastrointestinal tract. Therefore, the IndOH is responsible for antiendematogenic activity reported for IndOEt-NC.

Objetivos: Avaliar a farmacocinética do éster etílico de indometacina (IndOEt) em ratos Wistar, após sua administração oral (p.o) e intravenosa (i.v.) nas formas livre ou nanoencapsulada, e monitorar a formação de indometacina (IndOH) in vivo. Metodologia: Os protocolos experimentais foram aprovados pelo Comitê de Ética em Pesquisa da UFRGS (2005478). Nanocápsulas (NC) contendo IndOEt (IndOEt- NC) foram administradas p.o. (10 mg/kg) e i.v. bolus (5 mg/kg) a ratos machos Wistar (n = 5 a 7/grupo) e as concentrações plasmáticas de IndOEt e IndOH resultantes foram determinadas por CLAE com detecção por UV, empregando-se metodologia validada. Os grupos controle foram tratados com suspensão aquosa de IndOEt (10 mg/kg), com ou sem polissorbato 80, ou com IndOH pelas vias i.v. ou p.o. (10 mg/kg) (n = 7 a 11/grupo). Os perfis plasmáticos individuais foram avaliados por abordagem não-compartimental e compartimental utilizando os softwares Excel® 2003 e Scientist® 2.01, respectivamente, para a determinação dos parâmetros farmacocinéticos, que foram comparados estatisticamente utilizando-se teste “t” de Student ou ANOVA (α = 0,05). A avaliação do local de absorção p.o. de IndOEt-NC foi realizada pela quantificação de IndOEt e IndOH no plasma periférico e da veia porta, homogeneizado de fígado e de parede, bem como conteúdo, de porções do intestino delgado (n= 4/tempo) após a administração oral da formulação. Resultados e Discussão: Após a administração de IndOEt-NC por ambas as vias, apenas a IndOH foi detectada, indicando uma rápida hidrólise do éster. Em todos os casos, o IndOEt não alterou os parâmetros farmacocinéticos da IndOH, exceto a biodisponibilidade. Os perfis plasmáticos de IndOH i.v. foram descritos pelo modelo de 2 compartimentos, e os orais, pelo de 1 compartimento com absorção de primeira ordem. A avaliação da absorção oral de IndOEt-NC evidenciou que o IndOEt é, provavelmente, liberado e hidrolisado ainda na luz do trato gastrintestinal, sendo a IndOH formada in vivo e absorvida. Conclusões: O IndOEt nanoencapsulado ou não, quando administrado pelas vias oral e i.v., é rapidamente convertido a IndOH. A IndOH é, portanto, responsável pela atividade antiedematogênica relatada para o IndOEt-NC. / Objective: To evaluate the pharmacokinetics of either nanoencapsulated (NC) or free indomethacin ethyl ester (IndOEt) after intravenous (i.v.) and oral (p.o.) administration to Wistar rats and to determine the pharmacokinetics of indomethacin (IndOH) formation. Methodology: Animal experiments were approved by UFRGS Ethics in Research Committee (# 2005478). The pharmacokinetics was investigated in male Wistar rats after oral and i.v. administration of IndOEt-NC (10 mg/kg and 5 mg/kg, respectively) (n = 5-7/group) and IndOEt and IndOH plasma concentrations were determined by a validated HPLC with UV detection method. The control groups were treated with IndOEt aqueous suspension (10 mg/kg p.o.) or with IndOH aqueous suspension by the p.o. or i.v. routes (10 mg/kg) (n = 7 -11/group). Noncompartmental and compartmental approaches were used for individual profiles analysis using Excel® 2003 or Scientist® 2.01 softwares, respectively. The site of IndOEt-NC oral absorption was investigated in peripheral and portal vein plasma, hepatic tissue, intestine epithelia, and lumen content (n = 4/time). Results and Discussion: After IndOEt administration by both routes, only IndOH was detected in plasma, suggesting a fast hydrolysis of the ester. The IndOH parameters after administration of IndOEt and IndOH were similar, except for the bioavailability. The pharmacokinetic parameters of IndOH were modeled by two compartment open model after i.v. dosing and by one compartment with first order absorption after oral administration. After oral administration, IndOEt-NC was converted in IndOH in the gastrointestinal tract and then absorbed as such. Conclusions: After i.v. and oral administration, either IndOEt-NC or the free drug is quickly converted in IndOH. After oral administration, IndOEt-NC is released and hydrolyzed to IndOH following its absorption at the gastrointestinal tract. Therefore, the IndOH is responsible for antiendematogenic activity reported for IndOEt-NC.

Magister Pharmaceuticae - MPharm / The overall objective of this research is to attempt to produce, by direct compression, indomethacin tablets which have good dissolution characteristics and an improved bioavailability profile, when compared to the capsule formulations currently available. In order to use the direct compression method, the solubilized form of indomethacin should have good flow properties, as well as a small bulk volume for incorporation into reasonably sized tablets.

O objetivo da presente tese foi desenvolver um adesivo com nanocápsulas (NCs), contendo indometacina, e um sistema adesivo com nanocápsulas (NC), contendo indometacina e triclosan, e avaliar suas propriedades. As NCs foram produzidas por meio do método de deposição de polímero, secas e caracterizadas quanto ao tamanho de partículas, à forma, quantidade de fármaco encapsulado e citotoxicidade. Uma resina adesiva foi formulada. Foram adicionadas ao adesivo 1%, 2%, 5% e 10% de NCs em massa, e um grupo permaneceu sem NC. As NCs, contendo indometacina e triclosan, foram também incorporadas no primer comercial a 2% em peso e um grupo permaneceu sem NCs. Os adesivos foram avaliados quanto ao GC imediato e tardio, à degradação em solvente, liberação dos fármacos, difusão de indometacina pela dentina e resistência de união. O adesivo com 10% de NCs, contendo indometacina, foi também avaliado quanto à ação anti-inflamatória em modelo animal. O primer e o adesivo com as diferentes concentrações de NCs, contendo indometacina e triclosan, foram avaliados quanto à liberação dos fármacos, difusão de indometacina pela dentina, ao efeito antimicrobiano, grau de conversão (GC) in situ, ângulo de contato e à resistência de união à microtração. Os dados foram analisados por ANOVA, Tukey e teste t. As NCs apresentaram forma esférica e viabilidade celular acima de 80%. As NCs, contendo indometacina, apresentaram diâmetro médio de 165 nm e as NCs, contendo indometacina e triclosan, 159 nm. O adesivo, contendo 10% de NCs com indometacina, apresentou efeito anti-inflamatório. A incorporação de NCs não alterou o GC, que variou de 63,63 ± 1,01% a 70,50 ± 2,08%. A degradação em solvente não foi alterada com 2% de NCs. Tanto os adesivos quanto o primer apresentaram liberação controlada. A indometacina permeou através da dentina. O adesivo e primer também apresentaram efeito antimicrobiano. A incorporação de NCs no primer e no adesivo não influenciou o GC in situ nem a resistência de união imediata, em comparação aos materiais sem NCs. O uso concomitante do primer e adesivo com NCs aumentou o ângulo de contato e diminuiu a resistência de união longitudinal. Conclui-se que o uso do adesivo com a incorporação de NCs tem potencial para proporcionar ações terapêuticas à adesão dentinária. / The aim of the present thesis was to develop an adhesive with nanocapsules (NCs) containing indomethacin and an adhesive system with nanocapsules containing indomethacin and triclosan and to evaluate their properties. NCs were prepared by the interfacial deposition of preformed polymer technique, dried and characterized regarding particle size, encapsulated drug content and cytotoxicity. Adhesive resin was produced. Concentrations of 1%, 2%, 5% and 10% of NCs were added in the adhesive and a group was maintained with no NCs. Indomethacin and triclosan-loaded NCs were also incorporated into a commercial primer in a concentration of 2% and a group was maintained with no NCs. Adhesives were evaluated regarding immediate and late degree of conversion (DC), degradation in solvent, drug release, indomethacin diffusion through dentin and bond strength. The adhesive with 10% of NCs containing indomethacin was also evaluated regarding the anti-inflammatory effect in an animal model. Primer and adhesive with different concentrations of NCs containing indomethacin and triclosan were evaluated regarding drug release, indomethacin diffusion through dentin, antimicrobial effect, in situ degree of conversion, contact angle and bond strength. Data were analyzed through ANOVA, Tukey post-hoc and t-test.NCs presented a spherical shape and cell viability higher than 80%. NCs containing indomethacin presented an averaged size of 165 nm and NCs containing indomethacin and triclosan, 159 nm. The adhesive with 10% of NCs containing indomethacin presented anti-inflammatory effect. The incorporation of NCs presented no alteration of DC, varying from 63.63 ± 1.01% a 70.50 ± 2.08%. Degradation in solvent suffers no influence of NCs with 2% of NCs. Adhesives and primer presented controlled drug release. Indomethacin diffused through dentin. Adhesive and primer also presented an antimicrobial effect. The incorporation of NCs in adhesive and primer showed no influence on in situ DC and immediate bond strength compared to materials with no NCs. The use in combination of primer and adhesive with NCs resulted in higher contact angle and lower longitudinal bond strength. It is possible to conclude that the use adhesive with incorporation of NCs has potential to provide therapeutic effects on dentin adhesion.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / Ulcer can be defined as a chronic inflammatory disease of the stomach and duodenum, which appears as a lesion in the digestive tract, which extends through the mucosa muscle or more deeply. The ulcer usually occurs because of an imbalance between protective and agrssive factors of the mucosa. Esculin (ESC) (6.7-Dihydroxycoumarin-6-O-Glucoside) was evaluated in models ethanol or indomethacin-induced gastric lesions in mice. Esculin (12.5, 25 and 50 mg/kg, p.o.) significantly reduced gastric lesions induced by absolute ethanol (0.2 mL/animal) at 69.96, 72.94 and 79.33% respectively, showing no relationship dose-response at the doses studied. This gastroprotection was also evaluated microscopically showing that the ESC (25 mg/kg, p.o.) decreased the cell loss in the mucosa, submucosal edema and hemorrhage. Esculin (25 and 50 mg/kg, p.o.) also reduced significantly the gastric lesions induced by indomethacin (20 mg/kg, p.o.). Gastroprotective mechanism of ESC was examined in the dose of 25 mg/kg, in the model of gastric lesions induced by ethanol in mice. In animals pretreated with L-NAME (10 mg/kg, sc), an inhibitor of nitric oxide synthase, or with glibenclamide (5 mg/kg, i.p.), a drug that blocks ATP-dependent potassium channels, or indomethacin (10 mg/kg, p.o.), a nonselective inhibitor of cyclooxygenase, the gastroprotective effect of ESC was inhibited significantly, suggesting the involvement, at least in part, of nitric oxide, activation of potassium channels and endogenous prostaglandins in gastroprotective effect of ESC. Otherwise, the gastroprotective effect of ESC (25 mg/kg, p.o.) was not reversed in animals pretreated with capsazepine (5 mg/kg, i.p.), an antagonist of vanilloid receptor TRPV-1, demonstrating that there is activation of these receptors in the mechanism of action of ESC. This work was also evaluated the antioxidant mechanism of ESC as gastroprotective agent, against ethanol-induced lesions. Under our experimental conditions, the model of induction of ethanol injury caused changes in the antioxidant system of the gastric mucosa of mice as the decrease in the levels of sulfhydryl groups (GSH) and activity of superoxide dismutase (SOD), also showed increased activity catalase (CAT), the activity of myeloperoxidase (MPO) and the concentration of species that react with thiobarbituric acid (TBARS) as index of lipid peroxidation (LPO). Esculin in the model of ethanol did not interfere with the concentration of GSH, but increased SOD activity, allowed the restoration of normal CAT activity, normal levels of LPO and MPO activity. The data suggest that the ESC promotes gastroprotection against gastric lesions induced by ethanol or indomethacin in mice whose mechanisms include the involvement of endogenous prostaglandins, nitric oxide, and or, of KATP channels, as well as an antioxidant activity. / A Ãlcera pÃptica pode ser definida como sendo uma doenÃa inflamatÃria crÃnica do estÃmago e duodeno, que se apresenta como uma lesÃo na mucosa do trato digestivo, que se estende atravÃs da musculatura da mucosa ou mais profundamente. A Ãlcera pÃptica geralmente ocorre devido a um desequilÃbrio entre os fatores de defesa e agressores da mucosa. Este trabalho teve como objetivo avaliar a atividade gastroprotetora da esculina, (6,7-diidroxicumarina-6-o-glicosÃdio), e identificar os mecanismos farmacolÃgicos envolvidos. A esculina foi avaliada em modelos de lesÃes gÃstricas induzidas por etanol absoluto (0,2 mL/animal) em camundongos swiss, nas doses 12,5, 25 e 50 mg/kg, v.o., os resultados mostraram a reduÃÃo das lesÃes gÃstricas induzidas por etanol em 69,96, 72,94 e 79,33 % respectivamente, nÃo mostrando relaÃÃo dose-resposta nas doses estudadas. Esta gastroproteÃÃo tambÃm foi avaliada microscopicamente mostrando que a ESC (25 mg/kg, v.o.) diminuiu a perda celular na mucosa, formaÃÃo de edema na submucosa e hemorragia. A ESC (25 e 50 mg/kg, v.o.), tambÃm, foi avaliada no modelo de lesÃo gÃstrica induzida por indometacina (20 mg/Kg, v.o.), mostrando uma reduÃÃo das lesÃes gÃstricas. O mecanismo gastroprotetor da ESC foi analisado na sua dose de 25 mg/Kg, em modelo de lesÃes gÃstricas induzidas por etanol em camundongos. Em animais prÃ-tratados com L-NAME (10 mg/Kg, s.c.), um inibidor da Ãxido nÃtrico sintase, ou com glibenclamida (5 mg/Kg, i.p.), droga bloqueadora de canais de potÃssio ATP-dependentes, ou indometacina (10 mg/Kg, v.o.), um inibidor nÃo seletivo da ciclooxigenase, o efeito gastroprotetor da ESC foi inibido significativamente, sugerindo o envolvimento, pelo menos em parte, do Ãxido nÃtrico, ativaÃÃo dos canais de potÃssio e prostaglandinas endÃgenas no efeito gastroprotetor da ESC. De outra forma, o efeito gastroprotetor da ESC (25 mg/Kg, v.o.) nÃo foi revertido em camundongos prÃ-tratados com capsazepina (5 mg/Kg, i.p.), um antagonista dos receptores vanilÃides TRPV-1, demonstrando assim que nÃo hà ativaÃÃo destes receptores no mecanismo de aÃÃo da ESC. Neste trabalho tambÃm foi avaliado a aÃÃo antioxidante da ESC como mecanismo gastroprotetor contra as lesÃes induzidas por etanol. Sob nossas condiÃÃes experimentais, o modelo de induÃÃo de lesÃo por etanol provocou alteraÃÃo no sistema antioxidante da mucosa gÃstrica dos camundongos, como a diminuiÃÃo nos nÃveis de grupamentos sulfidrila (GSH) e atividade da superÃxido dismutase (SOD), tambÃm observamos aumento da atividade da catalase (CAT), da atividade da mieloperoxidase (MPO) e da concentraÃÃo de espÃcies que reagem com o Ãcido tiobarbitÃrico (TBARs), como Ãndice de peroxidaÃÃo lipÃdica (LPO). A ESC no modelo de etanol nÃo interferiu com a concentraÃÃo de GSH, mas aumentou a atividade da SOD, permitiu o restabelecimento da atividade normal da CAT e de patamares normais de LPO e de atividade da MPO. Os dados obtidos sugerem que a ESC promove gastroproteÃÃo contra as lesÃes gÃstricas induzidas por etanol ou indometacina em camundongos, por mecanismos que incluem o envolvimento de prostaglandinas endÃgenas, Ãxido nÃtrico, e ou, dos canais de KATP, alÃm de uma aÃÃo antioxidante.

O objetivo da presente tese foi desenvolver um adesivo com nanocápsulas (NCs), contendo indometacina, e um sistema adesivo com nanocápsulas (NC), contendo indometacina e triclosan, e avaliar suas propriedades. As NCs foram produzidas por meio do método de deposição de polímero, secas e caracterizadas quanto ao tamanho de partículas, à forma, quantidade de fármaco encapsulado e citotoxicidade. Uma resina adesiva foi formulada. Foram adicionadas ao adesivo 1%, 2%, 5% e 10% de NCs em massa, e um grupo permaneceu sem NC. As NCs, contendo indometacina e triclosan, foram também incorporadas no primer comercial a 2% em peso e um grupo permaneceu sem NCs. Os adesivos foram avaliados quanto ao GC imediato e tardio, à degradação em solvente, liberação dos fármacos, difusão de indometacina pela dentina e resistência de união. O adesivo com 10% de NCs, contendo indometacina, foi também avaliado quanto à ação anti-inflamatória em modelo animal. O primer e o adesivo com as diferentes concentrações de NCs, contendo indometacina e triclosan, foram avaliados quanto à liberação dos fármacos, difusão de indometacina pela dentina, ao efeito antimicrobiano, grau de conversão (GC) in situ, ângulo de contato e à resistência de união à microtração. Os dados foram analisados por ANOVA, Tukey e teste t. As NCs apresentaram forma esférica e viabilidade celular acima de 80%. As NCs, contendo indometacina, apresentaram diâmetro médio de 165 nm e as NCs, contendo indometacina e triclosan, 159 nm. O adesivo, contendo 10% de NCs com indometacina, apresentou efeito anti-inflamatório. A incorporação de NCs não alterou o GC, que variou de 63,63 ± 1,01% a 70,50 ± 2,08%. A degradação em solvente não foi alterada com 2% de NCs. Tanto os adesivos quanto o primer apresentaram liberação controlada. A indometacina permeou através da dentina. O adesivo e primer também apresentaram efeito antimicrobiano. A incorporação de NCs no primer e no adesivo não influenciou o GC in situ nem a resistência de união imediata, em comparação aos materiais sem NCs. O uso concomitante do primer e adesivo com NCs aumentou o ângulo de contato e diminuiu a resistência de união longitudinal. Conclui-se que o uso do adesivo com a incorporação de NCs tem potencial para proporcionar ações terapêuticas à adesão dentinária. / The aim of the present thesis was to develop an adhesive with nanocapsules (NCs) containing indomethacin and an adhesive system with nanocapsules containing indomethacin and triclosan and to evaluate their properties. NCs were prepared by the interfacial deposition of preformed polymer technique, dried and characterized regarding particle size, encapsulated drug content and cytotoxicity. Adhesive resin was produced. Concentrations of 1%, 2%, 5% and 10% of NCs were added in the adhesive and a group was maintained with no NCs. Indomethacin and triclosan-loaded NCs were also incorporated into a commercial primer in a concentration of 2% and a group was maintained with no NCs. Adhesives were evaluated regarding immediate and late degree of conversion (DC), degradation in solvent, drug release, indomethacin diffusion through dentin and bond strength. The adhesive with 10% of NCs containing indomethacin was also evaluated regarding the anti-inflammatory effect in an animal model. Primer and adhesive with different concentrations of NCs containing indomethacin and triclosan were evaluated regarding drug release, indomethacin diffusion through dentin, antimicrobial effect, in situ degree of conversion, contact angle and bond strength. Data were analyzed through ANOVA, Tukey post-hoc and t-test.NCs presented a spherical shape and cell viability higher than 80%. NCs containing indomethacin presented an averaged size of 165 nm and NCs containing indomethacin and triclosan, 159 nm. The adhesive with 10% of NCs containing indomethacin presented anti-inflammatory effect. The incorporation of NCs presented no alteration of DC, varying from 63.63 ± 1.01% a 70.50 ± 2.08%. Degradation in solvent suffers no influence of NCs with 2% of NCs. Adhesives and primer presented controlled drug release. Indomethacin diffused through dentin. Adhesive and primer also presented an antimicrobial effect. The incorporation of NCs in adhesive and primer showed no influence on in situ DC and immediate bond strength compared to materials with no NCs. The use in combination of primer and adhesive with NCs resulted in higher contact angle and lower longitudinal bond strength. It is possible to conclude that the use adhesive with incorporation of NCs has potential to provide therapeutic effects on dentin adhesion.

O objetivo da presente tese foi desenvolver um adesivo com nanocápsulas (NCs), contendo indometacina, e um sistema adesivo com nanocápsulas (NC), contendo indometacina e triclosan, e avaliar suas propriedades. As NCs foram produzidas por meio do método de deposição de polímero, secas e caracterizadas quanto ao tamanho de partículas, à forma, quantidade de fármaco encapsulado e citotoxicidade. Uma resina adesiva foi formulada. Foram adicionadas ao adesivo 1%, 2%, 5% e 10% de NCs em massa, e um grupo permaneceu sem NC. As NCs, contendo indometacina e triclosan, foram também incorporadas no primer comercial a 2% em peso e um grupo permaneceu sem NCs. Os adesivos foram avaliados quanto ao GC imediato e tardio, à degradação em solvente, liberação dos fármacos, difusão de indometacina pela dentina e resistência de união. O adesivo com 10% de NCs, contendo indometacina, foi também avaliado quanto à ação anti-inflamatória em modelo animal. O primer e o adesivo com as diferentes concentrações de NCs, contendo indometacina e triclosan, foram avaliados quanto à liberação dos fármacos, difusão de indometacina pela dentina, ao efeito antimicrobiano, grau de conversão (GC) in situ, ângulo de contato e à resistência de união à microtração. Os dados foram analisados por ANOVA, Tukey e teste t. As NCs apresentaram forma esférica e viabilidade celular acima de 80%. As NCs, contendo indometacina, apresentaram diâmetro médio de 165 nm e as NCs, contendo indometacina e triclosan, 159 nm. O adesivo, contendo 10% de NCs com indometacina, apresentou efeito anti-inflamatório. A incorporação de NCs não alterou o GC, que variou de 63,63 ± 1,01% a 70,50 ± 2,08%. A degradação em solvente não foi alterada com 2% de NCs. Tanto os adesivos quanto o primer apresentaram liberação controlada. A indometacina permeou através da dentina. O adesivo e primer também apresentaram efeito antimicrobiano. A incorporação de NCs no primer e no adesivo não influenciou o GC in situ nem a resistência de união imediata, em comparação aos materiais sem NCs. O uso concomitante do primer e adesivo com NCs aumentou o ângulo de contato e diminuiu a resistência de união longitudinal. Conclui-se que o uso do adesivo com a incorporação de NCs tem potencial para proporcionar ações terapêuticas à adesão dentinária. / The aim of the present thesis was to develop an adhesive with nanocapsules (NCs) containing indomethacin and an adhesive system with nanocapsules containing indomethacin and triclosan and to evaluate their properties. NCs were prepared by the interfacial deposition of preformed polymer technique, dried and characterized regarding particle size, encapsulated drug content and cytotoxicity. Adhesive resin was produced. Concentrations of 1%, 2%, 5% and 10% of NCs were added in the adhesive and a group was maintained with no NCs. Indomethacin and triclosan-loaded NCs were also incorporated into a commercial primer in a concentration of 2% and a group was maintained with no NCs. Adhesives were evaluated regarding immediate and late degree of conversion (DC), degradation in solvent, drug release, indomethacin diffusion through dentin and bond strength. The adhesive with 10% of NCs containing indomethacin was also evaluated regarding the anti-inflammatory effect in an animal model. Primer and adhesive with different concentrations of NCs containing indomethacin and triclosan were evaluated regarding drug release, indomethacin diffusion through dentin, antimicrobial effect, in situ degree of conversion, contact angle and bond strength. Data were analyzed through ANOVA, Tukey post-hoc and t-test.NCs presented a spherical shape and cell viability higher than 80%. NCs containing indomethacin presented an averaged size of 165 nm and NCs containing indomethacin and triclosan, 159 nm. The adhesive with 10% of NCs containing indomethacin presented anti-inflammatory effect. The incorporation of NCs presented no alteration of DC, varying from 63.63 ± 1.01% a 70.50 ± 2.08%. Degradation in solvent suffers no influence of NCs with 2% of NCs. Adhesives and primer presented controlled drug release. Indomethacin diffused through dentin. Adhesive and primer also presented an antimicrobial effect. The incorporation of NCs in adhesive and primer showed no influence on in situ DC and immediate bond strength compared to materials with no NCs. The use in combination of primer and adhesive with NCs resulted in higher contact angle and lower longitudinal bond strength. It is possible to conclude that the use adhesive with incorporation of NCs has potential to provide therapeutic effects on dentin adhesion.

Over the past few decades many researchers have investigated the utility of in vitro - in vivo correlations for the assessment of dosage forms. These investigations are, however, dependent on reproducible dissolution data and well conducted biostudies in order to establish meaningful and robust correlations. Despite the fact that the establishment of such correlations is perhaps idealistic, considerable interest has still been shown in this area of research. Various Controlled/Modified Release Dosage Forms (CMRD's) of theophylline, a weakly basic drug, and indomethacin, a weakly acidic drug, were assessed in order to establish in vitro - in vivo correlations. Dissolution rate studies were carried out using either the USP basket or paddle apparatus. The dissolution rate studies were conducted in a range of dissolution media of varying pH. Bioavailability studies were conducted on the dosage forms used by the Biopharmaceutics Research Institute at Rhodes University. The results of these biostudies were kindly made available for use in this research project. Type A correlations were established using a mathematical simulation process whereby expected in vivo responses are simulated and compared to actual profiles obtained for the dosage forms. In order to perform the simulations the dissolution rate profiles were stripped and using linear regression and the methods of residuals the dissolution rate order and the relevant dissolution rates were obtained. The results of the s imulations indicated that the in vivo serum concentration-time curves could be accurately predicted for the theophylline dosage forms but to a lesser extent, for the indomethacin formulations. The dissolution rate studies indicated that the paddle method is a suitable method for dissolution rate studies of theophylline CMRD's, although it appeared that the optimum pH of the dissolution medium was formulation dependent. Dissolution rate studies conducted on indomethacin formulations indicated that the USP specified basket method for extended-release indomethacin formulations was not able to distinguish between two formulations which exhibited different in vivo profiles. The conversion to the paddle method was, however, able to highlight the differences between these formulations. The use of three dimensional topographs to depict dissolution rate profiles was demonstrated for formulations of both theophylline and indomethacin. The topographs enabled the successful differentiation between bioinequivalent formulations. The dissolution rate profiles were also fitted to the Wei bull equation and the parameters obtained from this were compared to the Weibull parameters obtained from the in vivo absorption plots obtained using the Wagner-Nelson method. The results indicated that the Weibull function was suitable to describe both the in vivo and in vitro data. The following recommendations for the preformulation dissolution studies of weakly acidic and weakly basic drugs are proposed. The dissolution rate studies of weakly acid drugs, such as indomethacin, should be carried out over a range of pH utilising the paddle apparatus. Three dimensional topographs based on the dissolution data should be constructed and used as a comparative tool for different formulations. Based on these comparisons the appropriate formulation can then be selected for a pilot scale in vivo bioavailability study. The dissolution rate studies of weakly basic drugs, such as theophylline, should be carried out over a range of pH utilising the paddle apparatus. The dissolution data should then be used to simulate the expected in vivo profile and on this basis the appropriate formulation selected for a pilot scale bioavailability study. The above approach to the preformulation studies of new CMRO's would allow for the more careful selection of new dosage forms and could thus eliminate costly and unnecessary bioavailability studies performed on inferior formulations.

No description available.

Contents: Chitosan -- Controlled drug delivery -- Indomethacin -- Inotropic gelation -- Tripolyphosphate (TPP) -- Explotab® -- Ac-Di-Sol® -- Vitamin C / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.