Chemical degradation kinetics of fibrates: bezafibrate, ciprofibrate and fenofibrate

ABSTRACT Fibrates are drugs used for the treatment of hypertriglyceridemia and for the prevention of atherosclerosis. Three drugs in the fibrate class, ciprofibrate, fenofibrate and bezafibrate, were chosen for this study because their raw materials are readily available and because scientific publications on these compounds is limited. To evaluate their intrinsic stability, the drugs were exposed to a test condition (temperature, oxidation, UV light exposure, hydrolysis at different pH values and metal ions in solution) and then were subjected to analysis by HPLC. The samples were run on a C18 column, with a flow rate of 1.0 mL min-1 in a mobile phase consisting of methanol: 0.01 % phosphoric acid v/v (80:20), with variable detection wavelengths in the UV spectra. The analysis methodology showed satisfactory performance parameters. The three drugs were very unstable, degrading in each of the conditions evaluated. The test conditions of acid and basic hydrolysis showed the most significant degradation. The results demonstrated that the drugs in this class are unstable. Based on these experimentally determined degradation kinetics, it is easy to understand and emphasize the importance of the lack of liquid dosage forms on the market for fibrates because of their instability

Developing methods to compare tablet formulations of atorvastatin

Atorvastatin (ATV) is an antilipemic drug of great interest to the pharmaceutical industry. ATV does not appear in the monographs of Brazilian pharmacopoeia, and analytical methodologies for its determination have been validated. The chromatographic conditions used included: RP-18 column-octadecylsilane (250 x 4.6 mm, 5 mm), detection at 238 nm, mobile phase containing 0.1% phosphoric acid and acetonitrile (35:65% v/v), flow at 1.5 mL min-1, oven temperature at 30ºC, and injection volume of 10 mL. ATV is classified as a class II product, according to the biopharmaceutical classification system. As such, a dissolution test was proposed to evaluate pharmaceutical formulations on the market today, under the following conditions: water as a dissolution medium, 1000 mL as a volume, paddle apparatus at a rotation speed of 50 rpm, 80% (Q) in 15 minutes with UV spectrophotometer readings at 238 nm. In the pattern condition proposed as the ideal dissolution test, which appropriately differentiates amongst formulations, the generic product was not considered pharmaceutically equivalent; however, in other less differential dissolution methods, which also fall within appropriate legal parameters, this product could come to be regarded as generic.Atorvastatina (ATV) é um fármaco antilipêmico de grande interesse para a indústria farmacêutica. ATV não apresenta monografia na Farmacopéia Brasileira e metodologias analíticas para sua determinação foram validadas. As condições cromatográficas utilizadas foram: coluna RP-18-octadecilsilano (250 x 4.6 mm, 5 mm), detecção em 238 nm, fase móvel contendo ácido fosfórico 0,1% e acetonitrila (35:65% v/v), fluxo de 1,5 mL min-1, temperatura do forno de 30 ºC e volume de injeção de 10 mL. ATV é classificada como um fármaco de classe II, de acordo com o sistema de classificação biofarmacêutica (SCB). Como tal, um teste de dissolução foi proposto para avaliar as formulações farmacêuticas do mercado atual, sob as seguintes condições: água como meio de dissolução, volume de 1000 mL, aparato pá, velocidade de rotação de 50 rpm, 80% (Q) em 15 minutos com leituras espectrofotômetro UV a 238 nm. Na condição padrão proposta para o teste de dissolução, o qual seria capaz de diferenciar apropriadamente as formulações farmacêuticas, o produto genérico não foi considerado equivalente farmacêutico. No entanto, em outros métodos de dissolução menos discriminativos, que também seriam considerados apropriados pelos parâmetros legais, este produto pode vir a ser considerado como genérico

Self-emulsifying therapeutic system: a potential approach for delivery of lipophilic drugs

Self-emulsifying therapeutic system (SETs) provide an effective and intelligent solution to the various issues related to the formulation of hydrophobic drugs with limited solubility in gastrointestinal fluid. Although the potential utility of SETs is well known, only in recent years has a mechanistic understanding of the impact of these systems on drug disposition emerged. These in situ emulsion-forming systems have a high stability when incorporated in various dosage forms. SETs are being looked upon as systems which can overcome the problems associated with delivery of poorly water soluble drugs. An in-depth knowledge about lipids and surfactants that can contribute to these systems, criterion for their selection and the proportion in which they can be used, represent some crucial factors determining the in vivo performance of these systems. This article presents a comprehensive account of various types of self-emulsifying formulations with emphasis on their composition and examples of currently marketed preparations.O sistema terapêutico auto-emulsionante (SETs) fornece solução eficaz e inteligente para os vários problemas relativos à formulação de fármacos hidrofóbicos com solubilidade limitada no fluido gastrintestinal. Embora a utilidade potencial dos SETs seja bem conhecida, só recentemente se compreendeu, mecanisticamente,o impacto desses sistemas na disposição de fármacos. Estes sistemas de formação de emulsão in situ têm alta estabilidade, quando incorporados em várias formas de dosagem. Os SETs têm sido considerados como sistemas que podem resolver problemas associados à liberação de fármacos pouco solúveis em água. O conhecimento profundo dos lipídios e tensoativos que podem ser utilizados para estes sistemas e o critério para a sua seleção e proporção na qual eles são utilizados são alguns dos fatores cruciais que determinam o desempenho do sistema in vivo. Este artigo apresenta o relato abrangente de vários tipos de formulações auto-emulsificantes, com ênfase em sua composição e exemplos das preparações que são correntemente comercializadas

Pharmacokinetics and metabolism of 2-aminothiazoles with antiprion activity in mice

Purpose: To discover drugs lowering PrP in prion-infected cultured neuronal cells that achieve high concentrations in brain to test in mouse models of prion disease and then treat people with these fatal diseases. Methods: We tested 2-AMT analogs for EC and PK after a 40 mg/kg single dose and 40-210 mg/kg/day doses for 3 days. We calculated plasma and brain AUC, ratio of AUC/EC after dosing. We reasoned that compounds with high AUC/EC ratios should be good candidates going forward. Results: We evaluated 27 2-AMTs in single-dose and 10 in 3-day PK studies, of which IND24 and IND81 were selected for testing in mouse models of prion disease. They had high concentrations in brain after oral dosing. Absolute bioavailability ranged from 27-40%. AUC/EC ratios after 3 days were >100 (total) and 48-113 (unbound). Stability in liver microsomes ranged from 30->60 min. Ring hydroxylated metabolites were observed in microsomes. Neither was a substrate for the MDR1 transporter. Conclusions: IND24 and IND81 are active in vitro and show high AUC/EC ratios (total and unbound) in plasma and brain. These will be evaluated in mouse models of prion disease