Physicochemical characterization and thermal behavior of hexosomes containing ketoconazole as potential topical antifungal delivery system.

OBJECTIVE: The main purpose of this article is to show the valuable characteristics that liotropic liquid crystal systems possess to be employed as new drug delivery systems. SIGNIFICANCE: Colloidal aqueous dispersions of lyotropic liquid crystal mesophases such as the identified as cubosomes and hexosomes, and so on, have received considerable attention due to their unique nanostructures and their thermodynamic properties, which provide the potential as a sustained drug release matrix. Additionally, their large surface area and similarity with the liquid crystal structures of intercellular lipids of stratum corneum enhances the interaction with the skin and mucous, increasing the potential for topical drug delivery efficiency of biopharmaceutical class II drugs as the antifungal ketoconazole. METHODS: This article presents the results in morphological characteristics, particle size, ζ potential, flow, thermal behavior and drug release studies of hexosomes containing ketoconazole (LHLC-K) obtained with glycerol monooleate, propylene glycol monolaurate, poloxamer, and water mixtures. RESULTS: This colloidal system exhibits a Newtonian-type flow and a hexagonal nanostructure with a median particle size of 107 ± 20 nm and ζ potential of +4.45 ± 0.50 mV. Through differential scanning calorimetry studies, the LHLC-K demonstrated physical and chemical stability for more than six months and mesophasic thermal reversibility between 10 and 50 °C. Finally, LHLC-K releases ketoconazole following a kinetics described by the first order model. CONCLUSIONS: Physicochemical properties of the hexosomes containing ketoconazole are important for topical mycosis treatment administration, conditions of storage, and for its incorporation into the formulation of semi-solid dosage forms.

Rational use of antioxidants in solid oral pharmaceutical preparations

Antioxidants are currently used as efficient excipients that delay or inhibit the oxidation process of molecules. Excipients are often associated with adverse reactions. Stability studies can guide the search for solutions that minimize or delay the processes of degradation. The ability to predict oxidation reactions in different drugs is important. Methods: This study was conducted to assess the rational use of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite (SMB), propyl gallate (PG) and cysteine (CYS) in tablet formulations of simvastatin and ketoconazole. These antioxidants were evaluated according to stability parameters and the relationship between efficiency of the antioxidant and chemical structure of the drugs. Results were compared with DPPH tests and computational simulations. BHT was most efficient regarding simvastatin stability, and the most effective BHT concentrations for maintaining stability were 0.5 and 0.1%. In relation to ketoconazole, SMB was most efficient for maintaining content and dissolution profile. The evaluation by DPPH showed that the largest percentage of absorbance reduction was observed for PG, while SMB proved most efficient and had lower consumption of DPPH. The same pattern was observed, albeit with lower efficiency, for the other lipophilic antioxidants such as BHT and BHA. The results of the molecular modeling study demonstrated that electronic properties obtained were correlated with antioxidant activity in solution, being useful for the rational development of liquid pharmaceutical formulations but not for solid oral formulations. This study demonstrated the importance of considering stability parameters and molecular modeling to elucidate the chemical phenomena involved in antioxidant activity, being useful for the rational use of antioxidants in the development of pharmaceutical formulations.

Atualmente, antioxidantes são usados como excipientes eficientes, que retardam ou inibem o processo de oxidação de moléculas. Excipientes são frequentemente associados a efeitos adversos. Estudos de estabilidade podem ajudar na busca por possíveis soluções para minimizar ou retardar os processos de degradação. A habilidade de prever as reações de oxidação em diferentes fármacos é importante. O estudo foi conduzido com o objetivo de avaliar o uso racional de hidroxianisol butilado (BHA), hidroxitolueno butilado (BHT), metabissulfito sódico (SMB), galato de propila (PG) e cisteína (CYS) em formulações de comprimidos de sinvastatina e cetoconazol. Eles foram avaliados por parâmetros de estabilidade e pela relação entre a eficiência dos antioxidantes e a estrutura química do fármaco. Os resultados foram comparados com testes de DPPH e simulações em computador. BHT foi mais eficiente com relação a estabilidade da sinvastatina e às concentrações mais eficientes para manutenção de estabilidade foram 0,5 e 0,1%. Com relação ao cetoconazol, SMB foi mais eficiente em manter o conteúdo e o perfil de dissolução. A avaliação por DPPH mostrou que o maior percentual de redução de absorção foi observado para PG, enquanto que SMB mostrou ser mais eficiente e consumir menos DPPH. A mesma tendência foi observada com menos eficiência em todos os outros antioxidantes lipofílicos como o BHT e BHA. Os resultados do estudo de modelagem molecular demonstraram que as propriedades eletrônicas obtidas podem ser correlacionadas com a atividade antioxidante em solução, sendo útil para o desenvolvimento racional de formulações farmacêuticas líquidas, mas não para formulações sólidas orais. Este estudo demonstrou a importância de considerar parâmetros de estabilidade e modelagem molecular para elucidar os fenômenos químicos envolvidos na atividade antioxidante, sendo úteis para o uso racional de antioxidantes no desenvolvimento de formulações farmacêuticas.

Determination of ketoconazole in capsules by high-performance liquid chromatography and microbiological assay.

The development and validation of an HPLC-UV method and a microbiological assay were performed for the analysis of ketoconazole in capsule formulations. The bioassay was developed using a specific agar diffusion technique with the strain of Candida albicans ATCC 18804 as the test organism. The effect of the mobile phase pH in the range of 2.5-7.5 on the retention and tailing factors of the ketoconazole peak was analyzed in the chromatography method and a pH value of 4.5 was considered to be adequate. A prospective validation of both methods showed adequate linearity (r2 > 0.99 for the two methods), precision, (RSD = 2.42% for intraday and 2.69% for interday precision for bioassay; RSD = 0.74% for intraday and 0.66% for interday precision for HPLC-UV), and accuracy (mean recoveries were 103 +/- 1.0% for bioassay and 99 +/- 1.0% for HPLC-UV). Student's t-test revealed no significant difference between the results obtained by the two methods (P < 0.05). The contents found for three capsule samples showed a strong correlation, as attested by Pearson's coefficient value (r = 0.9998), which also evidenced the concordance between the studied methodologies.

Microbiological assay of ketoconazole in shampoo.

Ketoconazole, an anti-fungal agent, is often incorporated in several pharmaceutical forms and in shampoo formulation it is known to be effective against fungal infection on the scalp. This paper describes a method to quantify ketoconazole in shampoo by comparing the cylinder plate assay and the HPLC method. The test organism used for the agar diffusion assay was Candida albicans ATCC 10231. Three different concentrations of ketoconazole were used for the diffusion assay. A mean zone diameter was obtained for each concentration. A standard curve was obtained by plotting the three values derived from the zone diameters. A prospective validation of the method showed that the method was linear (r = 0.9982), precise (R.S.D. = 2.57%) and accurate. The results obtained by the two methods were statistically evaluated by analysis of variance (ANOVA) and the results obtained indicate that there is no significant difference between these two methods.

Comparison of fluconazole and ketoconazole in experimental murine blastomycosis

Fluconazole, anew oral triazole antifungal agent, was againts Blastomyces dermatitidis in vitro and in a murine model (pulmonary challenge) and compared with ketoconazole, an oral imidazole known to be effective against this agent in mice and in humans. Although fluconazole appeared less active than ketoconazole in vitro, in experiments involving 3 weeks of treatment and 2 months of observation, fluconazole was >10 times as potent (mg/kg) in vivo against blastomycosis (prolongation of life). In the model neither drug was curative at the doses and regimens used. A possible explanation for the efficacy of fluconazole in vivo is its favorable pharmacokinetic profile (i.e., prolonged serum concentrations that exceeded the MIC for the pathogen after oral administration. Dosages of 100 mg/(kg.d) were tolerated for 3 weeks without evidence toxicity

Evaluación multicéntrica de itraconazol en micosis vaginales / A multicenter evaluation of itraconazole in vaginal mycoses

Se evaluó la utilidad del empleo de Itraconazol 200 mg al día por tres días, en del tratamiento de 3013 pacientes con diagnóstico clínico de micosis vaginal en un estudio multicêntrico en gran escala con la participación de 686 investigadores. Se entrevistó al paciente tres veces durante el estudio y la evaluación final se hizo a los 30 días postratamiento. Los resultados consistentemente mostraron una eficacia superior al 90% tanto cuando se consideró el efecto sobre los signos y síntomas individuales como cuando se hizo una valoración global. Los resultados son igualmente buenos tratándose de casos agudos, crónicos o recurrentes. El perfil de efectos secundarios fueron mínimos, ya que su frecuencia es baja y el tipo de ellos no es alarmante