Development of parenteral formulations and evaluation of the biological activity of the trypanocide drug benznidazole

Lamas, María Celina; Villaggi, Luciano; Nocito, Isabel; Bassani, Georgina; Leonardi, Darío; Pascutti, María Fernanda; Serra, Esteban; Salomón, Claudio J.

doi:10.1016/j.ijpharm.2005.10.004

Cited by 56 publications

(59 citation statements)

References 18 publications

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“…In the case of ITC, its pharmacokinetics is influenced by its low solubility in water, approximately 100,000-fold less soluble than BNZ in neutral pH, which limits both the speed and level of absorption (16,19,22). The lower AUC values for ITC in this study are possibly a consequence of this fact.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Monitoring of Drug Association in Experimental Chemotherapy of Chagas' Disease by a New HPLC-UV Method

Silva

Oliveira

Silva-Barcellos

et al. 2012

Antimicrob Agents Chemother

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ABSTRACTA combination of drugs in experimental chemotherapy of Chagas' disease may increase the effectiveness of treatment. To evaluate the possible mechanisms that influence the improvement of therapy, we investigated the pharmacokinetic interaction between benznidazole and itraconazole in a murine model treated orally with single doses of 5 mg of each compound separately or together. Blood samples from treated mice were collected at different intervals for 48 h, and a high-performance liquid chromatography (HPLC)-UV method was used to quantify both drugs in the plasma. A decrease of 1.5-fold in the maximum drug concentration in the plasma (Cmax) and an increase of 2.66-fold in the volume of distribution (V) and 7.5-fold in the elimination half-life (t1/2β) of benznidazole when coadministered with itraconazole were observed. The parameters area under the curve (AUC0-t), area under the curve extrapolated to infinity (AUC0-∞), time to maximum concentration of drug in serum (Tmax), and clearance (CL) for benznidazole were not significantly different in this therapeutic regime. None of the evaluated parameters for ITC demonstrated a significant difference between isolated and associated administration. These results suggest that the main effect of this interaction leads to accumulation of benznidazole in the biological system. This effect may contribute to the improved therapeutic efficacy of this combination of drugs, in addition to synergism of the different mechanisms of action of benznidazole and itraconazole againstTrypanosoma cruzi in vivo.

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Section: Discussionmentioning

confidence: 99%

Preclinical Monitoring of Drug Association in Experimental Chemotherapy of Chagas' Disease by a New HPLC-UV Method

Silva

Oliveira

Silva-Barcellos

et al. 2012

Antimicrob Agents Chemother

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“…At this time, the only trypanocidal chemotherapeutic drugs available for CD are in solid dosage forms; therefore, pediatric formulations are still needed (Sosa-Estani et al 2005). Studies are being conducted to create new formulations in solution (Lamas et al 2006), suspension, and solid dissolvable tablet forms in pediatric concentrations (DNDi 2009).…”

Section: New Ways To Address Old Needsmentioning

confidence: 99%

Therapy, diagnosis and prognosis of chronic Chagas disease: insight gained in Argentina

Sosa-Estáni

Viotti²,

Segura

2009

Mem. Inst. Oswaldo Cruz

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“…Therefore, the primary task is to formulate a dosage form that contains the therapeutically effective dose of the active ingredient in a system that exhibits the least possible toxicity. In the case of liquid formulations comprising one or more active ingredients which show poor water solubility, solubility enhancers are often used to ensure the therapeutically effective dose of the compounds (3)(4)(5)(6)(7)(8)(9). The effect of such excipients on the pharmacokinetics of the drugs and their impact on the blood have been widely studied (10)(11)(12)(13) and although the toxicity of a formulation can by no means be explained solely by the concentration of the applied excipients, it is widely accepted that the lower the level of an excipient in a formulation, the less likely it is to induce toxicity.…”

Section: Introductionmentioning

confidence: 99%

Composition Optimization and Stability Testing of a Parenteral Antifungal Solution based on a Ternary Solvent System

et al. 2010

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Abstract. An intravenous solution is a dosage forms intended for administration into the bloodstream. This route is the most rapid and the most bioavailable method of getting drugs into systemic circulation, and therefore it is also the most liable to cause adverse effects. In order to reduce the possibility of side effects and to ensure adequate clinical dosage of the formulation, the primarily formulated composition should be optimized. It is also important that the composition should retain its therapeutic effectiveness and safety throughout the shelf-life of the product. This paper focuses on the optimization and stability testing of a parenteral solution containing miconazole and ketoconazole solubilized with a ternary solvent system as model drugs. Optimization of the solvent system was performed based on assessing the risk/ benefit ratio of the composition and its properties upon dilution. Stability tests were conducted based on the EMEA (European Medicines Agency) "guideline on stability testing: stability testing of existing active substances and related finished products". Experiments show that both the amount of co-solvent and surface active agent of the solvent system could substantially be reduced, while still maintaining adequate solubilizing power. It is also shown that the choice of various containers affects the stability of the compositions. It was concluded that by assessing the risk/benefit ratio of solubilizing power versus toxicity, the concentration of excipients could be considerably decreased while still showing a powerful solubilizing effect. It was also shown that a pharmaceutically acceptable shelf-life could be assigned to the composition, indicating good long-term stability.

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Development of parenteral formulations and evaluation of the biological activity of the trypanocide drug benznidazole

Cited by 56 publications

References 18 publications

Preclinical Monitoring of Drug Association in Experimental Chemotherapy of Chagas' Disease by a New HPLC-UV Method

Preclinical Monitoring of Drug Association in Experimental Chemotherapy of Chagas' Disease by a New HPLC-UV Method

Therapy, diagnosis and prognosis of chronic Chagas disease: insight gained in Argentina

Composition Optimization and Stability Testing of a Parenteral Antifungal Solution based on a Ternary Solvent System

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