Liquid chromatography-mass spectrometry for simultaneous determination of spironolactone and canrenone in plasma samples

Abstract n our study, we aimed to validate a method based on liquid chromatography-mass spectrometry (LC-MS) to quantify spironolactone (SPI) and its active metabolite canrenone (CAN) simultaneously in plasma samples to support in vivo experiments. Compounds were separated by using a C18 column with the isocratic elution of a mobile phase composed of 0.1% (v/v) formic acid in methanol-water (60:40 v/v) at a flow rate of 0.4 mL min−1. SPI and CAN were detected in na electrospray interface operating in a positive ionization mode and quantified using the selective ion mode monitoring of mass-charge ratios (m/z) of 439.0 for SPI and 363.1 for CAN. After calculating the matrix effect using theoretical equations, we observed the strong interference of plasma in the equipment-generated signal, which required creating analytical curves using the matrix as a solvent. The method was nevertheless linear (r 2 > 0.999) in a concentration range of 0.4-5.0 µg mL−1, as well as precise, with a coefficient of variation less than 5%. SPI's and CAN's recovery rates from the plasma ranged from 87.4% to 112.1%, while their limits of detection (i.e., 0.07 µg mL−1 and 0.03 µg mL−1, respectively) and quantification (i.e., 0.20 µg mL−1 and 0.08 µg mL−1, respectively) in the presence of plasma contaminants were low. Therefore, the bioanalytical method seems to be feasible for quantifying SPI and CAN in plasma

Compatibility and stability studies involving polymers used in fused deposition modeling 3D printing of medicines / 药物分析学报

One of the challenges in developing three-dimensional printed medicines is related to their stability due to the manufacturing conditions involving high temperatures.This work proposed a new pro-tocol for preformulation studies simulating thermal processing and aging of the printed medicines,tested regarding their morphology and thermal,crystallographic,and spectroscopic profiles.Gener-ally,despite the strong drug-polymer interactions observed,the chemical stability of the model drugs was preserved under such conditions.In fact,in the metoprolol and Soluplus? composition,the drug's solubilization in the polymer produced a delay in the drug decomposition,suggesting a pro-tective effect of the matrix.Paracetamol and polyvinyl alcohol mixture,in turn,showed unmistakable signs of thermal instability and chemical decomposition,in addition to physical changes.In the presented context,establishing protocols that simulate processing and storage conditions may be decisive for obtaining stable pharmaceutical dosage forms using three-dimensional printing technology.

Topical ophthalmic antimicrobials: unfulfilled demands and possibility of new investments in Brazil and in the United States

In general, topical ophthalmic drug products, especially those used for treating infections, present low effectiveness because of various reasons, from unfavorable drug physicochemical properties to physiological protective mechanisms of the eye. The fact is such group of products holds room for improvement, which could mean the development of better drugs or dosage forms. To achieve this, the knowledge of market composition is essential. The present work studied and compared the antimicrobial ophthalmic markets of Brazil and of the United States (US). Official databank of Brazilian Health Regulatory Agency and of US Food and Drug Administration were assessed for registered antimicrobial topical ophthalmic drug products. Brazilian market has registered greater number of drug products (119) than the US (94), but the latter involves more variety of substances and dosage forms. In both countries, non-innovative products registered as solutions of antibacterials, especially fluoroquinolones and aminoglycosides lead the market. Despite the clinical demand, the US has only one group of antimycotics (polyenes) registered, while in Brazil, there is not any ophthalmic antimycotic product marketed. This study evidences there is not only space for development of newer drugs and formulations but also a demand for already existing technologies and products in both countries.

Panorama dos aspectos regulatórios que norteiam a partição de comprimidos / Overview of regulatory aspects guiding tablet scoring

RESUMO A partição de comprimidos é uma prática controversa no meio da saúde. Mesmo assim, é amplamente difundida, principalmente em tratamentos envolvendo crianças e idosos, para ajustar doses, facilitar a ingestão do medicamento ou baratear o custo do tratamento medicamentoso. Os riscos dessa prática estão relacionados principalmente à imprecisão na dosagem das frações e a problemas de estabilidade no medicamento partido. O objetivo deste trabalho foi traçar um panorama das bases sanitárias que norteiam esse tema no mundo. Constatamos que as agências regulatórias de saúde dos países que integram o Mercosul, além de outros países sul-americanos, não possuem normas publicadas que tratem de partição de comprimidos. Entre as agências sanitárias pesquisadas, a Food and Drug Administration (FDA), nos Estados Unidos, é a única a apresentar normas que abrangem desde instruções para orientar o fracionamento até a regulação do processo de fabricação. O conceito de sulco funcional implementado pela FDA estabelece algumas garantias quanto à capacidade do comprimido de ser fracionado. Pode-se concluir que ainda faltam bases técnicas e científicas para direcionar as normas sanitárias acerca desse tema, tornando a decisão sobre a partição de comprimidos, em determinadas situações, aleatória e de alto risco para a saúde pública. A necessidade de regulação mais pormenorizada é vital para garantir a segurança dos usuários de medicamentos.

ABSTRACT Tablet scoring is a controversial but common practice used to adjust doses, facilitate drug intake, or lower the cost of drug treatment, especially in children and the elderly. The risks of tablet scoring are mainly related to inaccuracies in the resulting dose and stability problems. The aim of this article is to provide an overview of worldwide guidelines regarding tablet scoring. We found that regulatory health agencies in Mercosur countries as well as other South American countries do not have published standards addressing tablet splitting. Among the surveyed health agencies, the Food and Drug Administration (FDA) in the United States is the only one to present standards, ranging from splitting instructions to regulation of the manufacturing process. The concept of functional scoring implemented by the FDA has introduced some level of guarantee as to the ability of tablets to be split. In conclusion, technical and scientific bases are still insufficient to guide health rules on this subject, making the decision on scoring, in certain situations, random and highly risky to public health. The need for more detailed regulation is vital to ensure the safety of tablet medications.

Injeção sem agulhas: aplicações médicas e perspectivas futuras / Needle-free injection: medical applications and future perspectives

Numerosos inconvenientes da administração de formulações farmacêuticas empregando agulhas e seringas têm impulsionado enorme investimento na pesquisa de novos mecanismos de administração. Uma das opções tecnológicas mais promissoras são os sistemas de injeção sem agulha, e alguns modelos são disponíveis no mercado. Esses sistemas, que incluem injetores de jato de formulações líquidas e injetores de pó, são dispositivos adaptados para a administração de diferentes tipos de fármacos e vacinas através da pele de maneira minimamente invasiva. A administração cutânea de vacinas é vantajosa, pois aumenta a resposta imunitária, elimina riscos de contaminação cruzada, facilita o ato da vacinação, o processo de descarte e, portanto, reduz os custos. Esta revisão se dedica a abordar as vantagens do uso dos sistemas semagulha em terapêutica, discutindo-se mecanismos de ação, vantagens e obstáculos para seu uso, diferenças entre os tipos de injetores, bem como aplicações e perspectivas futuras.

The various disadvantages of administering pharmaceutical formulations using needles and syringes have led to a huge investment in researchabout new delivery mechanisms. One of the most promising technological alternatives is the needlefree injection system. In fact, some models are already available in the market. These systems, which include liquid and powder jet injectors, are devices adapted for drug and vaccine administration through the skin in a minimally invasive manner. Topical vaccine administration is advantageous because it increases the immune response and eliminates cross-contamination risks. It also facilitates vaccination and the disposal process, thus reducing costs. This review aims at addressing the advantages of needle-free systems in therapy by discussing their mechanisms of action, the advantages of and obstacles to their use, differences between the types of injectors, and their applicationsand future perspectives.

Development and physical evaluation of Maytenus ilicifolia effervescent granules using factorial design

The medicinal plant Maytenus ilicifolia is a commonly used phytomedicine for the treatment of gastritis. The high dose required and low density of these extracts make necessary a daily intake of several capsules, hindering adherence to the medication. The purpose of this work was to develop a suitable dosage form for the administration of Maytenus ilicifolia using effervescent granules. A 23 factorial design was used to study the physical characteristics of the granules (particle size distribution, repose angle, Carr index, scanning electron microscopy and disintegration time). Moisture stability was also determined. According to the experimental design, granule size is the most important factor in determining the flow characteristics of effervescent granules. In turn, the disintegration time is controlled by the content of sodium bicarbonate present in the effervescent mixture as well as the granule size. The stability of formulations when exposed to moisture is strongly influenced by the percentage of effervescent mixture present in the vegetal granules. Precautions in handling and storage should be taken to ensure the stability of these preparations. The effervescent granules produced from Maytenus ilicifolia met the pharmacopoeial quality parameters, with appropriate mechanical and physical characteristics and proved to be a promising vehicle for plant extracts.

A planta medicinal Maytenus ilicifolia é comumente empregada como fitoterápico no tratamento da gastrite. As elevadas doses requeridas e a baixa densidade dos extratos dessa planta levam à ingestão diária de várias cápsulas do medicamento, dificultando a adesão ao tratamento. A proposta desse trabalho foi desenvolver uma forma farmacêutica adequada para administração de Maytenus ilicifolia usando granulados efervescentes. Um desenho fatorial 23 foi empregado para estudar as características físicas dos granulados (distribuição dos tamanhos de partícula, ângulo de repouso, índice de Carr, microscopia eletrônica de varredura e tempo de desintegração). A higroscopicidade das preparações também foi estudada. De acordo com o desenho experimental, o tamanho de partícula é o fator mais importante para a determinação das características de fluxo dos granulados efervescentes. Em contrapartida, o tempo de desintegração é controlado pelo conteúdo de bicarbonato de sódio presente na mistura efervescente, assim como pelo tamanho do granulado. A estabilidade das formulações quando expostas à umidade é fortemente influenciada pelo percentual de mistura efervescente presente nos granulados. Precauções de manipulação e armazenamento devem ser tomadas para garantir a estabilidade dessas preparações. Os granulados efervescentes produzidos com Maytenus ilicifolia cumprem os requisitos farmacopeicos de qualidade, com adequadas características físicas e mecânicas, provando ser um veículo promissor para extratos vegetais.

Recentes avanços no tratamentoda doença de Chagas / Recent advances in the treatment of Chagas disease

Descoberta há cem anos, a doença de Chagas afetaa mais de quinze milhões de pessoas em toda aAmérica Latina e, ainda hoje, não há tratamentoeficaz. O fármaco benznidazol, utilizado como únicaopção de tratamento no Brasil, é ineficaz na fasecrônica da doença. Problemas relacionados à biodisponibilidadedo medicamento comercial limitam suaeficácia, principalmente na fase crônica, quando osparasitos estão confinados em tecidos profundos eem lenta replicação. Nesse contexto, pesquisas lideradaspor grupos brasileiros e argentinos vêm sendoconduzidas com o objetivo de desenvolver formulaçõesde benznidazol mais eficientes. Diversas formasfarmacêuticas sólidas e líquidas foram propostas nosúltimos anos com resultados pré-clínicos promissores,sendo descritas melhorias acentuadas nas característicasfarmacocinéticas desse fármaco. Espera-seque as formas inovadoras apresentadas possam seravaliadas em ensaios clínicos e incorporadas à produçãoindustrial em breve.

Discovered about a hundred years ago, Chagas diseasecurrently affects more than fifteen million people in LatinAmerica, and it still remains without any effective treatment.Although benznidazole has been used as the onlypharmacotherapeutic option to treat Chagas disease inBrazil, it is ineffective in the chronic phase of the disease,when the parasites are confined to deep tissue layers andslowly replicate. This happens mainly due to problems related to the bioavailability of the drug, which is currentlyin the market. In this context, Brazilian and Argentineanresearch groups have conducted studies to develop moreefficient benznidazole formulations. Several solid andliquid formulations have been proposed over the last fewyears with promising preclinical results. Improvementsin the pharmacokinetic properties of this drug have beendescribed. Therefore, it is expected, that such innovative drugs and formulations be assessed in clinical trials andsoon incorporated to industrial production.

Co-processed extracts of Cassia angustifolia Vahl, Fabaceae, and Maytenus ilicifolia (Schrad.) Planch., Celastraceae, for production of high load tablets

The aim of this study was to investigate the feasibility of a co-processing technique for improving the manufacturing properties of Maytenus ilicifolia (Schrad.) Planch., Celastraceae, and Cassia angustifolia Vahl, Fabaceae, extracts in order to obtain tablets containing a high dose of such extracts. An experimental mixture design was used to optimise the formulation composition. Flowability parameters, such as compressibility index, time flow and angle of repose, were determined. Additional important industrial parameters, such as granulometry, bulk density and moisture stability, were also studied. The results demonstrated that co-processing technique was able to improve the flowability of vegetal extracts, making these materials suitable for a direct compression process. The contour plots revealed that formulations with a higher amount of lactose produced the best flow results as well as a larger particle size and a greater bulk density. Tablets from co-processed extracts containing lactose as majority diluent showed appropriate physical-chemical characteristics and presented a more stable moisture sorption behaviour compared to commercial gelatine capsules.