RESUMO
The aim of this work was to develop indinavir pediatric anti-HIV/AIDS formulations enabling convenient dose adjustment, ease of oral administration, and improved organoleptic properties by means of the generation of drug-loaded microparticles made of a polymer that is insoluble under intake conditions and dissolves fast in the stomach in order to completely release the active agent. Indinavir-loaded microparticles made of a pH-dependent polymeric excipient soluble at pH < 5, Eudragit E100, were prepared using a double emulsion solvent diffusion technique and the in vitro release profiles characterized. Finally, taste masking properties were evaluated in blind randomized sensory experiments by ten healthy human volunteers. The use of a w/o/o emulsion system resulted in indinavir loads around 90%. Thermal analysis of the microparticles by differential scanning calorimetry revealed that indinavir appeared mainly dispersed at the molecular level. Concentrations of residual organic solvents as determined by gas chromatography were below the upper limits specified by the European Pharmacopeia for pharmaceutical oral formulations. Then, the behavior of drug-containing microparticles in aqueous media at different pH values was assessed. While they selectively dissolved in gastric-like medium, in tap water (intake conditions), the matrix remained almost unchanged and efficiently prevented drug dissolution. Finally, sensoring taste tests performed by volunteers indicated that systems with indinavir loads approximately 15% displayed acceptable taste. This work explored the production of indinavir-containing microparticles based on a common pharmaceutical excipient as a means for the improvement of medicines of drugs involved in the treatment of HIV/AIDS. For systems containing about 15% drug, taste studies confirmed the acceptability of the formulation. In pediatric regimes, this composition would require an acceptable amount of formulation (0.7-1.5 g).
Assuntos
Acrilatos/química , Portadores de Fármacos , Inibidores da Protease de HIV/administração & dosagem , Indinavir/administração & dosagem , Adesão à Medicação , Polímeros/química , Paladar/efeitos dos fármacos , Administração Oral , Varredura Diferencial de Calorimetria , Química Farmacêutica , Criança , Composição de Medicamentos , Emulsões , Suco Gástrico/química , Inibidores da Protease de HIV/química , Humanos , Concentração de Íons de Hidrogênio , Indinavir/química , Cinética , Tamanho da Partícula , Projetos Piloto , Solubilidade , Tecnologia Farmacêutica/métodosRESUMO
An optimization, statistically based on t-student test, to set up dissolution test conditions for indinavir sulfate capsules is presented. Three dissolution media, including that reported in United States Pharmacopeial Forum, and two apparatus, paddle and basket, were applied. Two different indinavir sulfate capsules, products A and B, were evaluated. For a reliable statistical analysis eighteen capsules were assayed in each condition based on the combination of dissolution medium and apparatus. All tested media were statistically equivalent (P > 0.05) for both drug products when paddle apparatus was employed at the stirring speed of 50 rpm. The use of basket apparatus at the stirring speed of 50 rpm caused significant decrease in the drug release percent for the product B (P < 0.05). The best dissolution conditions tested, for products A and B, were applied to evaluate capsules dissolution profiles. Twelve dosage units were assayed and dissolution efficiency concept was used, for each condition, to obtain results with statistical significance (P > 0.05). Optimal conditions to carry out the dissolution test were 900 ml of 0.1 M hydrochloric acid as dissolution medium, basket at 100 rpm stirring speed and 260 nm ultraviolet detection.
Assuntos
Inibidores da Protease de HIV/química , Indinavir/química , Cápsulas , Estudos de Avaliação como Assunto , Farmacopeias como Assunto , Solubilidade , Tecnologia FarmacêuticaRESUMO
A simple, fast and reliable capillary electrophoresis (CE) method for determination of indinavir sulfate, a potent protease inhibitor used in human immunodeficiency virus (HIV) therapy, in commercial and simulated capsule formulations is described. The analysis was performed in a 75microm i.d. uncoated fused-silica capillary with 27cm length (effective length of 19.4cm) using a 20mmoll-1 phosphate buffer at pH 2.52. Samples were injected hydrodynamically by applying 0.5psi pressure during 2s. The applied voltage was 28kV. Direct UV detection at 214nm led to an adequate sensitivity without interference from sample excipients and known impurities. For quantitative purposes, diazepam was used as internal standard. Under optimized conditions, the migration times for indinavir sulfate and diazepam were 1.06 and 1.66min, respectively. Analytical curve of peak area ratios versus concentration in the range of 20.0-100.0microg/ml gave a coefficient of correlation of 0.9992, establishing the method linearity. The limits of detection and quantitation were 4.61 and 14.0microg/ml, respectively. The within-day precision expressed as relative standard deviation was <1.5% for 10 consecutive sample injections. An average recovery of 100.81+/-0.56% at three concentration levels was obtained. Based on the performance characteristics, the proposed methodology was found suitable for the determination of indinavir sulfate in capsule formulations, presenting additional advantages inherent to the CE technology, such as low consumption of reagents and column endurance.