Andréa Inês Horn Adams

Clotrimazole-loaded Eudragit® RS100 nanocapsules: preparation, characterization and in vitro evaluation of antifungal activity against Candida species.

Clotrimazole is a common choice for the treatment of vulvovaginal infections, but its low solubility and some side effects pose a challenge to its application. This work evaluated the feasibility to formulate clotrimazole-loaded cationic nanocapsules using Eudragit® RS100 and medium chain triglycerides as polymer and oily core, respectively, by the method of interfacial deposition of a preformed polymer. The physicochemical characteristics of nanocapsule formulations were evaluated at 0 day and 60 days after preparation. Particle size, zeta potential, polydispersity index, pH and drug content were stable during this period. In addition, nanocapsules were able to protect clotrimazole from photodegradation under UV radiation. By the dialysis bag diffusion technique, the nanosized formulations showed prolonged release of clotrimazole by anomalous transport and first order kinetics. A microbiological study was carried out by the microdilution method and showed that nanocapsules (mean size: 144 nm; zeta potential: +12 mV) maintained the antifungal activity of clotrimazole against Candida albicans and Candida glabrata strains susceptible and resistant to fluconazole.

Dithranol-loaded lipid-core nanocapsules improve the photostability and reduce the in vitro irritation potential of this drug

Dithranol is a very effective drug for the topical treatment of psoriasis. However, it has some adverse effects such as irritation and stain in the skin that make its application and patient adherence to treatment difficult. The aims of this work were to prepare and characterize dithranol-loaded nanocapsules as well as to evaluate the photostability and the irritation potential of these nanocarriers. Lipid-core nanocapsules containing dithranol (0.5 mg/mL) were prepared by interfacial deposition of preformed polymer. EDTA (0.05%) or ascorbic acid (0.02%) was used as antioxidants. After preparation, dithranol-loaded lipid-core nanocapsules showed satisfactory characteristics: drug content close to the theoretical concentration, encapsulation efficiency of about 100%, nanometric mean size (230-250 nm), polydispersity index below 0.25, negative zeta potential, and pH values from 4.3 to 5.6. In the photodegradation study against UVA light, we observed a higher stability of the dithranol-loaded lipid-core nanocapsules comparing to the solution containing the free drug (half-life times around 4 and 1h for the dithranol-loaded lipid-core nanocapsules and free drug solution containing EDTA, respectively; half-life times around 17 and 7h for the dithranol-loaded lipid-core nanocapsules and free drug solution containing ascorbic acid, respectively). Irritation test by HET-CAM method was conducted to evaluate the safety of the formulations. From the results it was found that the nanoencapsulation of the drug decreased its toxicity compared to the effects observed for the free drug.

Development and validation of a stability-indication LC-UV method for determination of daptomycin injectable form and kinetic study in alkaline medium

An isocratic liquid chromatography method (LC-UV) was developed and validated to determine daptomycin in injectable form. The method was carried out in a Waters XBridge C18 column (250 mm × 4.6 mm, 5 μm). The mobile phase was composed of methanol–acetonitrile–buffer (pH 2.2) (40 : 30 : 30 v/v/v) at a flow rate of 1.0 mL−1, using photodiode array (PDA) detection at 223 nm. The retention time obtained for daptomycin was 6.1 min and the method was linear in the range of 10 to 50 μg mL−1 (r = 0.9999). Forced degradation studies were performed to verify the specificity and stability-indicating capability of the method. The degradation kinetics under alkaline conditions were also evaluated. The method showed suitable accuracy (99.17%) and precision (RSD 0.59%) A two level full factorial design was used to determine the method robustness. The proposed method was applied for the analysis of daptomycin injectable form, contributing to the improvement of the quality control of this pharmaceutical product.

Investigation of β-cyclodextrin-norfloxacin inclusion complexes. Part 1. Preparation, physicochemical and microbiological characterization.

Introduction: Drugs classified as class IV by the Biopharmaceutical Classification System present significant problems in relation to effective oral administration. In the case of antibiotics, the subsequently high doses required can enhance the emergence of microorganism resistance and lead to a low rate of patient treatment adherence. Objective: In an attempt to improve physicochemical properties and microbiological activity of norfloxacin, the aim of this study was to investigate different methods (coevaporation, kneading followed by freeze-drying or spray-drying) to obtain complexes of norfloxacin and different cyclodextrins. Methods: Guest–host interactions were investigated through a complete physical–chemical characterization and the dissolution profile and microbiological activity were determined. Results: The formation of a complex of norfloxacin and β-cyclodextrin (1:1), obtained by kneading followed by freeze drying, led to increased drug solubility, which could maximize the oral drug absorption. Conclusion: Moreover, the microbiological activity was enhanced by around 23.3%, demonstrating that the complex formed could represent an efficient drug delivery system.

Desenvolvimento de um método para a determinação de tioconazol associado a nanocápsulas poliméricas por cromatografia líquida

The aim of this work was to develop and validate an analytical method for the quantification of tioconazole in polymeric nanocapsule suspensions by high performance liquid chromatography with UV detection. The analysis was performed with a mobile phase composed of methanol:water (80:20) and 0.18% ammonium hydroxide; RP-18 column and UV detection at 219 nm. The method proved to be linear in the concentration range of 5-50 µg mL-1 (r = 0.9999), specific, precise (repeatability RSD = 1.42%, intermediate precision RSD = 1.17%), accurate (98 - 102%) and robust (RSD < 2.0%). In conclusion, a simple and rapid method was validated proving suitable for quantification of tioconazole in polymeric nanocapsules.

ASSAY AND PHOTODEGRADATION KINETICS OF DESONIDE LOTION BY AN LC-UV STABILITY-INDICATING METHOD

This work describes the development and validation of an LC stability-indicating method for the quantitation of desonide lotion, followed by a photostability study of the same pharmaceutical form under exposure to UVA light (352 nm). The method used a RP-18 column, mobile phase composed of a methanol:acetonitrile:water pH 5.0 mixture (50:10:40) and detection at 244 nm. The method validation followed the ICH guidelines, and its robustness was evaluated by a factorial design (24). All the validation requirements were met, evidenced by good linearity (r > 0.9999, in the range from 10 to 100 µg/mL), accuracy (mean recovery 100.09%), precision (intra-day RSD 1.4 and 1.75%; inter-day RSD 1.59%), robustness, and specificity. The last one was indicated by high peak purity index in all the stress conditions adopted and by good resolution between the analite peak from adjacent peaks (R > 2.0). These data confirm the procedure suitability to routine analysis and stability studies. About the photodegradation of desonide lotion, it can be described by second-order kinetics with a t90% value of 1.58 h under the experimental conditions employed in this study. The low photostability of the product evaluated justifies the need for further studies aimed at improving the formulation in order to ensure safety and therapeutic efficacy.

Stability indicating RP-LC-PDA method for the quantitative analysis of saxagliptin in pharmaceutical dosage form

Saxagliptin is a potent and selective inhibitor of the enzyme dipeptidyl peptidase 4. It is effective in the treatment of type 2 diabetes mellitus because it stimulates the pancreas to produce insulin. In the present study, a liquid chromatography method was developed and validated to quantify the drug in tablets. This method was based on the isocratic elution of saxagliptin, using a mobile phase consisting of 0.1% phosphoric acid at pH 3.0 - methanol (70: 30, v/v) at a flow rate of 1 mL.min-1 with UV detection at 225 nm. The chromatographic separation was achieved in 8 minutes on a Waters XBridge C18 column (250 mm x 4.6 mm, 5µm) maintained at ambient temperature. The proposed method proved to be specific and robust for the quality control of saxagliptin in pharmaceutical dosage forms, showing good linearity in the range of 15.0 - 100.0 µg.mL-1 (r>0.999), precision (RSD<1.49%) and accuracy values between 99.42 and 101.59%. The method was found to be stability indicating and was successfully applied for the analysis of saxagliptin in tablets in a routine quality control laboratory.

A fully validated microbiological assay for daptomycin injection and comparison to HPLC method

A daptomicina (DPT) e o primeiro lipopeptideo ciclico disponivel para comercializacao. Possui atividade frente a bacterias gram-positivas, incluindo cepas resistentes. O objetivo deste trabalho foi desenvolver e validar um ensaio microbiologico turbidimetrico para quantificar a daptomicina na forma injetavel. Empregou-se delineamento 3x3, nas concentracoes de 1,0; 2,0 e 4,0 µg/mL. Como micro-organismo teste foi usado Staphylococcus aureus ATCC 6538p, e Meio para Antibioticos no 3 foi empregado como meio de cultura. A validacao do metodo demonstrou que o ensaio foi linear (r=0,9995), preciso (RSD=2,55%), exato (recuperacao de 100,48 ± 2,11%) e robusto. A cinetica de degradacao em meio alcalino foi avaliada, indicando que a daptomicina segue cinetica de primeira ordem nessa condicao. A analise das solucoes degradadas mostrou que os produtos de degradacao da daptomicina nao possuem atividade antimicrobiana. O bioensaio foi comparado com o metodo por CLAE previamente desenvolvido e nao houve diferenca significativa entre ambos (p<0,05). O metodo mostrou-se apropriado para o controle de qualidade da daptomicina injetavel.

Determination of dronedarone in the pharmaceutical dosage form by a stability-indicating micellar electrokinetic chromatography method

In this study, a micellar electrokinetic chromatography method was developed and validated for the analysis of dronedarone in film-coated tablets. Electrophoretic conditions were investigated by changing factors such as pH, buffer concentration, SDS concentration, capillary temperature, injection time and applied voltage. Separation was performed using a bare fused-silica capillary of 40.0 cm effective length (48.5 cm total length; 50 μm internal diameter) maintained at 30 °C and detection was set at 216 nm. Optimal conditions were obtained using 40 mM borate buffer and 50 mM SDS at pH 9.2 as running buffer with an applied voltage of 28 kV (positive polarity) and using hydrodynamic injection at 50 mbar for 7 s. The method was validated by evaluating typical validation characteristics such as specificity, linearity, accuracy, precision, the limit of detection, the limit of quantitation and robustness. The analytical curve was linear in the concentration range of 25 to 150 μg mL−1 (r = 0.9995). The accuracy was 99.9% and the relative standard deviations of repeatability and intermediate precision were lower than 2%. The limit of detection and limit of quantitation were 0.88 μg mL−1 and 2.66 μg mL−1, respectively. The method proved to be robust by a fractional factorial design evaluation. Forced degradation studies were performed by exposing dronedarone sample solution to stress conditions (acidic, basic, oxidative, thermal and photolytic) in order to verify the stability-indicating capability of the method. The MEKC method was successfully applied for the quality control of dronedarone hydrochloride in commercial film-coated tablets.

INIBIDORES DA BOMBA DE PRÓTONS: REVISÃO E ANÁLISE FARMACOECONÔMICA

Os inibidores da bomba de protons (IBPs), sao medicamentos que inibem a enzima H + , K + -ATPase (ou bomba de protons) realizando a supressao acida gastrica. Atualmente, sao comercializados seis representantes desta classe: omeprazol, lansoprazol, pantoprazol, rabeprazol, esomeprazol e dexlansoprazol. Um novo IBP, tenatoprazol, esta ainda em fase de desenvolvimento. O presente estudo propoe-se a revisar os estudos disponiveis a fim de expor informacoes sobre os IBPs e realizar um estudo farmacoeconomico entre doses-padrao desses medicamentos para o tratamento da ulcera peptica gastroduodenal. Evidencias atuais sugerem que os IBPs possuem eficacia semelhante no tratamento de varias desordens gastricas e no protocolo de erradicacao do Helicobacter pylori . A partir da analise farmacoeconomica ora realizada, constatou-se que o lansoprazol apresenta perfil mais favoravel.