The use of the SeDeM diagram expert system for the formulation of Captopril SR matrix tablets by direct compression

The SeDeM Diagram Expert System has been used to study excipients, Captopril and designed formulations for their galenic characterization and to ascertain the critical points of the formula affecting product quality to obtain suitable formulations of Captopril Direct Compression SR Matrix Tablets. The application of the Sedem Diagram Expert System enables selecting excipients with in order to optimize the formula in the preformulation and formulation studies. The methodology is based on the implementation of ICH Q8, establishing the design space of the formula with the use of experiment design, using the parameters of the SeDeM Diagram Expert System as system responses.

Estudos de formulação de solo‐cimento e solo‐cal e respectivas aplicações

Este trabalho teve como objectivo descrever os aspectos mais relevantes, ligados ao tratamento de solos com cimento e ao melhoramento de solos com cal, com um destaque particular para a aplicação das técnicas num contexto de obras rodoviárias. Pretende‐se também, descrever a metodologia dos estudos de formulação em laboratório cujo objectivo é optimizar a percentagem de ligante hidráulico a utilizar no melhoramento ou tratamento dos solos. É também objectivo, descrever a aplicação das referidas técnicas em contexto de obra, bem como o controlo da qualidade das mesmas. Os casos práticos apresentados neste trabalho referem‐se a duas obras realizadas pela empresa Mota‐Engil, sendo que a soluçãorelacionada com o tratamento de solos com cimento foi aplicada numa obra rodoviária em regime de concessão na zona norte do país, enquanto que a solução de melhoramento de solos com cal foi aplicada numa obra aeroportuária localizada no aeroporto de Lisboa.

Caracterização laboratorial de misturas betuminosas com incorporação de agregado siderúrgico inerte para construção (ASIC)

Trabalho Final de Mestrado para obtenção do grau de Mestre em Engenharia Civil na Área de Especialização de Vias de Comunicação e Transportes

Purificação e caracterização da beta-lapachona e estudo de estabilidade dos cristais em diferentes condições de armazenamento

The beta-lapachone is a product obtained from the Ipê Roxo tree [Tabebuia avellandae], which has proved its excellent antineoplasic potential acting through a particular mechanism of apoptosis against various cancer types. This study aims at determining the identity card of beta-lapachone by means of physico-chemical and pharmaco-technical characterization. A purifying process has been performed, as well as the isolation of a contaminant, its isomer alpha-lapachone. A stability study was also performed, determining the ideal storing conditions for beta-lapachone, essential for the ongoing pre-formulation studies for obtaining the different classic pharmaceutical forms and modified release systems.

Development of an ex vivo human skin model for intradermal vaccination : tissue viability and Langerhans cell behaviour

The presence of resident Langerhans cells (LCs) in the epidermis makes the skin an attractive target for DNA vaccination. However, reliable animal models for cutaneous vaccination studies are limited. We demonstrate an ex vivo human skin model for cutaneous DNA vaccination which can potentially bridge the gap between pre-clinical in vivo animal models and clinical studies. Cutaneous transgene expression was utilised to demonstrate epidermal tissue viability in culture. LC response to the culture environment was monitored by immunohistochemistry. Full-thickness and split-thickness skin remained genetically viable in culture for at least 72 h in both phosphate-buffered saline (PBS) and full organ culture medium (OCM). The epidermis of explants cultured in OCM remained morphologically intact throughout the culture duration. LCs in full-thickness skin exhibited a delayed response (reduction in cell number and increase in cell size) to the culture conditions compared with split-thickness skin, whose response was immediate. In conclusion, excised human skin can be cultured for a minimum of 72 h for analysis of gene expression and immune cell activation. However, the use of split-thickness skin for vaccine formulation studies may not be appropriate because of the nature of the activation. Full-thickness skin explants are a more suitable model to assess cutaneous vaccination ex vivo.

Thermal behavior and stability of biodegradable spray-dried microparticles containing triamcinolone

Thermal analysis has been widely used for obtaining information about drug-polymer interactions and for pre-formulation studies of pharmaceutical dosage forms. In this work, biodegradable microparticles Of Poly (D,L-lactide-co-glycolide) (PLGA) containing triamcinolone (TR) in various drug:polymer ratios were produced by spray drying. The main purpose of this study was to study the effect of the spray-drying process not only on the drug-polymer interactions but also on the stability of microparticles using differential scanning calorimetry (DSC), thermogravimetry (TG) and derivative thermogravimetry (DTG), X-ray analysis (XRD), and infrared spectroscopy (IR). The evaluation of drug-polymer interactions and the pre-formulation studies were assessed using the DSC, TG and DTG, and IR. The quantitative analysis of drugs entrapped in PLGA microparticles was performed by the HPLC method. The results showed high levels of drug-loading efficiency for all used drug: polymer ratio, and the polymorph used for preparing the microparticles was the form B. The DSC and TG/DTG profiles for drug-loaded microparticles were very similar to those for the physical mixtures of the components. Therefore, a correlation between drug content and the structural and thermal properties of drug-loaded PLGA microparticles was established. These data indicate that the spray-drying technique does not affect the physico-chemical stability of the microparticle components. These results are in agreement with the IR analysis demonstrating that no significant chemical interaction occurs between TR and PLGA in both physical mixtures and microparticles. The results of the X-ray analysis are in agreement with the thermal analysis data showing that the amorphous form of TR prevails over a small fraction of crystalline phase of the drug also present in the TR-loaded microparticles. From the pre-formulation studies, we have found that the spray-drying methodology is an efficient process for obtaining TR-loaded PLGA microparticles. (C) 2008 Elsevier B.V. All rights reserved.

Thermal analysis of biodegradable microparticles containing ciprofloxacin hydrochloride obtained by spray drying technique

Thermal analysis has been extensively used to obtain information about drug-polymer interactions and to perform pre-formulation studies of pharmaceutical dosage forms. In this work, biodegradable microparticles of poly(D,L-lactide-co-glycolide) (PLGA) containing ciprofloxacin hydrochloride (CP) in various drug:polymer ratios were obtained by spray drying. The main purpose of this study was to investigate the effect of the spray drying process on the drug-polymer interactions and on the stability of microparticles using differential scanning calorimetry (DSC), thermogravimetry (TG) and derivative thermogravimetry (DTG) and infrared spectroscopy (IR). The results showed that the high levels of encapsulation efficiency were dependant on drug:polymer ratio. DSC and TG/DTG analyses showed that for physical mixtures of the microparticles components the thermal profiles were different from those signals obtained with the pure substances. Thermal analysis data disclosed that physical interaction between CP and PLGA in high temperatures had occurred. The DSC and TG profiles for drug-loaded microparticles were very similar to the physical mixtures of components and it was possible to characterize the thermal properties of microparticles according to drug content. These data indicated that the spray dryer technique does not affect the physicochemical properties of the microparticles. In addition, the results are in agreement with IR data analysis demonstrating that no significant chemical interaction occurs between CP and PLGA in both physical mixtures and microparticles. In conclusion, we have found that the spray drying procedure used in this work can be a secure methodology to produce CP-loaded microparticles. (C) 2007 Elsevier B.V. All rights reserved.

Thermal behavior and stability of biodegradable spray-dried microparticles containing triamcinolone

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Thermal analysis of biodegradable microparticles containing ciprofloxacin hydrochloride obtained by spray drying technique

Thermal analysis has been extensively used to obtain information about drug-polymer interactions and to perform pre-formulation studies of pharmaceutical dosage forms. In this work, biodegradable microparticles of poly(D,L-lactide-co-glycolide) (PLGA) containing ciprofloxacin hydrochloride (CP) in various drug:polymer ratios were obtained by spray drying. The main purpose of this study was to investigate the effect of the spray drying process on the drug-polymer interactions and on the stability of microparticles using differential scanning calorimetry (DSC), thermogravimetry (TG) and derivative thermogravimetry (DTG) and infrared spectroscopy (IR). The results showed that the high levels of encapsulation efficiency were dependant on drug:polymer ratio. DSC and TG/DTG analyses showed that for physical mixtures of the microparticles components the thermal profiles were different from those signals obtained with the pure substances. Thermal analysis data disclosed that physical interaction between CP and PLGA in high temperatures had occurred. The DSC and TG profiles for drug-loaded microparticles were very similar to the physical mixtures of components and it was possible to characterize the thermal properties of microparticles according to drug content. These data indicated that the spray dryer technique does not affect the physicochemical properties of the microparticles. In addition, the results are in agreement with IR data analysis demonstrating that no significant chemical interaction occurs between CP and PLGA in both physical mixtures and microparticles. In conclusion, we have found that the spray drying procedure used in this work can be a secure methodology to produce CP-loaded microparticles. (C) 2007 Elsevier B.V. All rights reserved.

Estudos de pré-formulação e formulação de Heliotropium indicum (L.) DC (Boraginaceae)

Heliotropium indicum L. (Boraginaceae) é um subarbusto que atinge até 70 cm de altura, é amplamente distribuído geograficamente. A espécie é conhecida como fedegoso na região norte e nordeste. Diante do potencial biológico desta espécie este trabalho objetiva determinar parâmetros de qualidade da droga vegetal até o produto final e avaliar a atividade antimicrobiana de suas folhas, com finalidade de se obter uma formulação fitoterápica semi-sólida. Para isso utilizou-se parâmetros de controle de qualidade físico, químico e físico-químico descritos na Farmacopéia Brasileira e literatura pertinente. A droga vegetal foi classificada como pó grosso, apresentou valores médios de perda por dessecação e cinzas totais de 12,88% e 17,14%, respectivamente. A análise termogravimétrica do pó e do extrato liofilizado mostrou que ambos apresentaram boa estabilidade térmica até 180°C. Os espectros na região do IV mostraram um aumento na intensidade das bandas de absorção do extrato liofilizado, que pode está relacionado à extração dos constituintes químicos da matriz celular. A prospecção química do extrato confirmou a presença de classes de metabólitos secundários já relatados em literatura. A fração clorofórmica sugere a presença de alcalóides pelo teste de precipitação com reagente de Dragendorff. A CCD e a CLAE mostraram uma possível presença de uma mesma substância nas frações alcaloídicas e hexânicas. O extrato bruto de H. indicum L. inibiu o crescimento de Staphylococcus aureus apresentando halos de 12,5 mm±0,707 e 10,5 mm±0,707 para as concentrações de 500 mg/mL e 250 mg/mL, respectivamente. As misturas físicas do extrato com os adjuvantes farmacêuticos, utilizados no desenvolvimento da formulação fitoterápica, não apresentaram incompatibilidade física e não houve modificações significativas no perfil de absorção entre os compostos analisados. A formulação fitoterápica semi-sólida manteve-se estável após sua preparação, após a submissão do gel a força centrípeta e após ação do estresse térmico.

Excipient characterization and particle engineering to develop directly compressed orally disintegrating tablets

ODTs have emerged as a novel oral dosage form with a potential to deliver a wide range of drug candidates to paediatric and geriatric patients. Compression of excipients offers a costeffective and translatable methodology for the manufacture of ODTs. Though, technical challenges prevail such as difficulty to achieve suitable tablet mechanical strength while ensuring rapid disintegration in the mouth, poor compressibility of preferred ODT diluent Dmannitol, and limited use for modified drug-release. The work investigates excipients’ functionality in ODTs and proposes new methodologies for enhancing material characteristics via process and particle engineering. It also aims to expand ODT applications for modified drug-release. Preformulation and formulation studies employed a plethora of techniques/tests including AFM, SEM, DSC, XRD, TGA, HSM, FTIR, hardness, disintegration time, friability, stress/strain and Heckel analysis. Tableting of D-mannitol and cellulosic excipients utilised various compression forces, material concentrations and grades. Engineered D-mannitol particles were made by spray drying mannitol with pore former NH4HCO3. Coated microparticles of model API omeprazole were prepared using water-based film forming polymers. The results of nanoscopic investigations elucidated the compression profiles of ODT excipients. Strong densification of MCC (Py is 625 MPa) occurs due to conglomeration of physicomechanical factors whereas D-mannitol fragments under pressure leading to poor compacts. Addition of cellulosic excipients (L-HPC and HPMC) and granular mannitol to powder mannitol was required to mechanically strengthen the dosage form (hardness >60 N, friability <1%) and to maintain rapid disintegration (<30 sec). Similarly, functionality was integrated into D-mannitol by fabrication of porous, yet, resilient particles which resulted in upto 150% increase in the hardness of compacts. The formulated particles provided resistance to fracture under pressure due to inherent elasticity while promoted tablet disintegration (50-77% reduction in disintegration time) due to porous nature. Additionally, coated microparticles provided an ODT-appropriate modified-release coating strategy by preventing drug (omeprazole) release.

Pharmacological and local toxicity studies of a liposomal formulation for the novel local anaesthetic ropivacaine

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Development of a topical formulation containing S. Lutea extract: Stability, in vitro studies and cutaneous permeation

Flavonoids have been widely incorporated into cosmetic and dermatological formulations, affording benefits such as antioxidant action, improved skin tone and fewer lines and wrinkles. Brazil has a huge biodiversity, with one of the richest flora in the world, and existing studies justify the quest for greater research efforts in this area. The cajazeira (Spondias lutea L.), a plant of the Anacardiaceae family from tropical America, is widely disseminated in Brazil. This plant was chosen because of the presence of flavonoids that exhibit antioxidant activity. The purpose of this research was to develop a stable topical formulation containing Spondias lutea extract with the aim of preventing skin diseases caused by UV radiation. Hydro ethanolic extract of Spondias lutea fruit was prepared and assayed for its the flavonoids content. The antioxidant activity was estimated by DPPH and superoxide assay. The physicochemical stability and skin permeation of the cream containing 8% (w/w) of extract were assessed. The results showed that the S. lutea extract possessed antioxidant activity, and that it is possible to obtain a stable cosmetic containing the extract, which is able to penetrate the skin. Thus, it is possible to use this extract to produce an anti-aging cosmetic.

Studies to develop and investigate an inverse formulation for numerically solving three-dimensional free surface potential fluid flows,

Research carried out under Naval Ship Systems Command, General Hydromechanics Research Program, subproject SR 009 01 01, administered by the Naval Ship Research and Development Center, contract no. N00014-67-A-0220-0003.

Lipoplexes formulation and optimisation:in vitro transfection studies reveal no correlation with in vivo vaccination studies

The aim of these studies was to compare the effect of liposome composition on physico-chemical characteristics and transfection efficacy of cationic liposomes both in vitro and in vivo. Comparison between 4 popularly used cationic lipids, showed 3b-N-(dimethylaminoethyl)carbamate (DC-Chol) to promote the highest transfect levels in cells in vitro with levels being at least 6 times higher than those of 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA). 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and dimethyldioctadecylammonium (DDA) and approximately twice as efficient as dipalmitoyl-trimethylammonium-propane (DPTAP). To establish the role of the helper lipid, DC-Chol liposomes were formulated in combination with either 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE) or cholesterol (Chol) (1:1 molar ratio) with and without the addition of phosphatidyl choline. The choice of helper lipid incorporated within the bilayer was found to influence the formation of complexes, their resultant structure and their transfection efficiency in vitro, with SUV-DNA complexes containing optimum levels of DOPE giving higher transfection than those containing cholesterol. The inclusion of PC within the formulation also reduced transfection efficiency in vitro. However, when administered in vivo, SUV-DNA complexes composed of PC:Chol:DC-Chol at a molar ratio of 16:8:4 micromole/ml were the most effective at inducing splenocyte proliferation upon exposure to antigen in comparison to control spleens. These results demonstrate that there is no in vitro/in vivo correlation between the transfection efficacy of these liposome formulations and in vitro transfection in the above cell model cannot be taken as a reliable indicator for in vivo efficacy of DNA vaccines.