7 research outputs found
Effect of drug incorporation technique and polymer combination on the performance of biopolymeric antifungal buccal films
Numerous films with a dissolved or dispersed active principle within a polymeric matrix have been described in literature. However, the incorporation of solid crystals into the films may influence several relevant properties. Additionally, it has been reported that different polymeric matrices lead to films presenting a different performance. The aim of this work was to evaluate the effect of the combination of chitosan with carrageenan (Îș-, λ-, and Îč-) as matrices, and of the miconazole nitrate incorporation method, on the films behavior. Mechanical properties, drug release and antifungal activity were evaluated. The state of the drug in the films was analyzed by different techniques. Films showed a homogeneous surface and a thermal protective effect on the drug. The combination of chitosan and λ-carrageenan leads to films with the highest values of tensile and mucoadhesive strength. Films with solubilized drug displayed slightly higher elongation at break, tensile and mucoadhesive strength and faster drug release than those with suspended miconazole nitrate. However, no differences were found regarding the antifungal activity of the different formulations including time-to-kill curves.Fil: Tejada Jacob, Guillermo Ivan. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; ArgentinaFil: Lamas, Maria Celina. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Svetaz, Laura Andrea. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; ArgentinaFil: Salomon, Claudio Javier. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Alvarez, Vera Alejandra. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Leonardi, DarĂo. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; Argentin
Development and optimization of a new tioconazole vaginal mucoadhesive film using an experimental design strategy. Physicochemical and biological characterization
A new tioconazole (TCZ) mucoadhesive film, based on a biodegradable chitosan/ hydroxypropyl methylcellulose (CH/HPMC) blend, was developed for treatment of vaginal candidiasis. The formulation was optimized through an I-optimal design (minimizing the integral of the prediction variance across the factor space), where the impact of the proportion of the ingredients and processing variables on the quality of the final product was evaluated. Both, the thickness of the film and the swelling index, which affect patientsâ comfort and compliance, were considered. Mechanical testing, such as load at break, elongation at break, and mucoadhesive strength were also included as dependent variables. The optimal mucoadhesive film formulation, which should be obtained at a drying temperature of 30 °C, was found to include the combination of CH and HPMC (forming polymers) at 0.25:0.75 ratio, a mixture of polyethylene glycol 400 and propylene glycol as plasticizers (0.07:0.93, 5% w/w), and TCZ loaded at 15 % w/w. The optimal preparation was subjected to exhaustive characterization studies, which revealed that the drug was entrapped in the polymeric matrix in an amorphous state and that the film exhibited a smooth and uniform surface, demonstrating excellent component compatibility. In vitro tests showed that the formulation has an excellent time to kill value (3 min) and lacks cytotoxicity, suggesting that it should be highly effective and safe.Fil: Calvo, Natalia Lorena. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; ArgentinaFil: Tejada Jacob, Guillermo Ivan. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; Argentina. Universidad Nacional de Rosario; ArgentinaFil: Svetaz, Laura Andrea. Universidad Nacional de Rosario; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Quiroga, Ariel Dario. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de FisiologĂa Experimental. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de FisiologĂa Experimental; ArgentinaFil: Alvarez, Vera Alejandra. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de FisiologĂa Experimental. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de FisiologĂa Experimental; ArgentinaFil: Lamas, Maria Celina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y TecnologĂa de Materiales. Universidad Nacional de Mar del Plata. Facultad de IngenierĂa. Instituto de Investigaciones en Ciencia y TecnologĂa de Materiales; ArgentinaFil: Leonardi, DarĂo. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y TecnologĂa de Materiales. Universidad Nacional de Mar del Plata. Facultad de IngenierĂa. Instituto de Investigaciones en Ciencia y TecnologĂa de Materiales; Argentina. Universidad Nacional de Rosario; Argentin
Miconazole Nitrate Microparticles in Lidocaine Loaded Films as a Treatment for Oropharyngeal Candidiasis
Oral candidiasis is an opportunistic infection that affects mainly individuals with weakened immune system. Devices used in the oral area to treat this condition include buccal films, which present advantages over both oral tablets and gels. Since candidiasis causes pain, burning, and itching, the purpose of this work was to develop buccal films loaded with both lidocaine (anesthetic) and miconazole nitrate (MN, antifungal) to treat this pathology topically. MN was loaded in microparticles based on different natural polymers, and then, these microparticles were loaded in hydroxypropyl methylcellulose-gelatin-based films containing lidocaine. All developed films showed adequate adhesiveness and thickness. DSC and XRD tests suggested that the drugs were in an amorphous state in the therapeutic systems. Microparticles based on chitosan-alginate showed the highest MN encapsulation. Among the films, those containing the mentioned microparticles presented the highest tensile strength and the lowest elongation at break, possibly due to the strong interactions between both polymers. These films allowed a fast release of lidocaine and a controlled release of MN. Due to the latter, these systems showed antifungal activity for 24 h. Therefore, the treatment of oropharyngeal candidiasis with these films could reduce the number of daily applications with respect to conventional treatments.Fil: Tejada Jacob, Guillermo Ivan. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y TecnologĂa de Materiales. Universidad Nacional de Mar del Plata. Facultad de IngenierĂa. Instituto de Investigaciones en Ciencia y TecnologĂa de Materiales; ArgentinaFil: Calvo, Natalia Lorena. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Departamento de QuĂmica OrgĂĄnica; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario; ArgentinaFil: Morri, Mauro Gaspar. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - BahĂa Blanca. Planta Piloto de IngenierĂa QuĂmica. Universidad Nacional del Sur. Planta Piloto de IngenierĂa QuĂmica; ArgentinaFil: Sortino, Maximiliano AndrĂ©s. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Departamento de QuĂmica OrgĂĄnica. Ărea Farmacognosia; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario; ArgentinaFil: Lamas, Maria Celina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Departamento de Farmacia; ArgentinaFil: Alvarez, Vera Alejandra. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y TecnologĂa de Materiales. Universidad Nacional de Mar del Plata. Facultad de IngenierĂa. Instituto de Investigaciones en Ciencia y TecnologĂa de Materiales; ArgentinaFil: Leonardi, DarĂo. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Departamento de Farmacia; Argentin
Composite Microparticles Based on Natural Mucoadhesive Polymers with Promising Structural Properties to Protect and Improve the Antifungal Activity of Miconazole Nitrate
Oropharyngeal candidiasis is a recurrent oral infection caused by Candida species. Gel formulation containing miconazole nitrate is the most common approach for treating oral candidiasis. However, traditional oral topical antifungal therapies have many limitations, including short contact time with the oral mucosa and the necessity to administrate various doses per day. Thus, the aim of this work was to formulate composited microparticulated systems based on combinations of mucoadhesive cationic, anionic, and nonionic polymers that could protect and modify the drug release rate and therefore avoid a fast dilution of the drug by saliva. Microparticulated systems were prepared by the spray drying method employing chitosan, gelatin, and hydroxypropyl methylcellulose. The morphology of the systems was investigated by scanning electron microscopy; drug crystallinity was studied by X-ray, while interactions between polymers were analyzed by infrared spectroscopy. Drug release and halo zone test were employed to analyze the release and activity of the systems loaded with miconazole against Candida albicans cultures. The most appropriate microparticulated system was the one based on chitosan and gelatin which showed homogeneous morphology (mean size of 1.7 ± 0.5 Όm), a protective effect of the drug, and better antifungal effect against Candida culture than miconazole nitrate and the other assayed systems. Taking into account these results, this approach should be seriously considered for further evaluation of its safety and in vivo efficacy to be considered as an alternative therapeutic system for the treatment of oral candidiasis.Fil: Tejada Jacob, Guillermo Ivan. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; ArgentinaFil: Lamas, Maria Celina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; ArgentinaFil: Sortino, Maximiliano AndrĂ©s. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Alvarez, Vera Alejandra. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y TecnologĂa de Materiales. Universidad Nacional de Mar del Plata. Facultad de IngenierĂa. Instituto de Investigaciones en Ciencia y TecnologĂa de Materiales; ArgentinaFil: Leonardi, DarĂo. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; Argentin
A Novel Prototype Device for Microencapsulation of Benznidazole: In Vitro/In Vivo Studies
This study was aimed to design a simple and novel prototype device for the production of polymeric microparticles. To prove the effectiveness of this device, benznidazole microparticles using chitosan as carrier and NaOH, KOH, or SLS as counter ions were used. For comparison, benznidazole microparticles were prepared by the conventional dripping technique (syringe and gauge) using the same excipients. Microparticles were characterized in terms of encapsulation efficiency, particle shape, size and surface topography, crystallinity characteristics, thermal behavior, and dissolution rate. Then, the pharmacokinetic parameters were evaluated after the oral administration of the microparticles to healthy Wistar rats. The prepared formulations, by means of this device, showed good drug encapsulation efficiency (> 70%). Release studies revealed an increased dissolution of benznidazole from chitosan microparticles prepared using the novel device. It achieved more than 90% in 60 min, while those of the conventional microparticles and raw drug achieved 65% and 68%, respectively, during the same period. Almost spherical benznidazole microparticles with a smooth surface and size around 10â30 Όm were observed using scanning electron microscopy. Thermal analysis and X-ray diffraction studies suggested a partial reduction of drug crystallinity. Moreover, the relative oral bioavailability of the novel benznidazole microparticles showed that the area under the curve for the microencapsulated drug was 10.3 times higher than the raw drug. Thus, these findings indicate that the designed glass prototype device is a useful alternative to formulate benznidazole polymeric microparticles with improved biopharmaceutical properties and could be useful for other therapeutic microparticulate systems.Fil: Barrera, Maria Gabriela. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas; ArgentinaFil: Tejada Jacob, Guillermo Ivan. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; ArgentinaFil: Leonardi, DarĂo. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; ArgentinaFil: Lamas, Maria Celina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; ArgentinaFil: Salomon, Claudio Javier. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; Argentin
Formulation and in-vitro efficacy of antifungal mucoadhesive polymeric matrices for the delivery of miconazole nitrate
Oral candidiasis is the most common opportunistic infection affecting patients with the human immunodeficiency virus. Miconazole buccal tablets or miconazole gel are approved for the treatment of oropharyngeal candidiasis. However, buccal films present more flexibility and also offer protection for the wounded mucosa, reducing pain. Due to their small size and thickness, buccal films may improve patients' compliance, compared to tablets. Additionally, they may increase the relatively short residence time on the mucosa of oral gels, which are easily removed by saliva. Polymeric films loaded with miconazole nitrate were prepared by a casting/solvent evaporation methodology using chitosan, carbopol, gelatin, gum arabic, and alginate to form the polymeric matrices. The morphology of films was investigated by scanning electron microscopy; interactions between polymers were analyzed by infrared spectroscopy and drug crystallinity by differential thermal analysis and X-ray diffraction. Films were characterized in terms of thickness, folding endurance, tensile properties, swelling, adhesiveness, and drug release. Finally, the antifungal activity against cultures of the five most important fungal opportunistic pathogens belonging to Candida genus was investigated. The more appropriate formulations were those based on chitosan-gelatin and chitosan-carbopol which showed good mechanical properties and adhesiveness, a relative low swelling index, improved drug release, and showed better in vitro activity against Candida cultures than miconazole nitrate raw material. Thus, it will be possible to produce a new pharmaceutical form based on polymeric films containing chitosan and miconazole nitrate, which could be loaded with low drug concentration producing the same therapeutic effect against Candida cultures.Fil: Tejada Jacob, Guillermo Ivan. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; ArgentinaFil: Piccirilli, Gisela Noemi. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas; ArgentinaFil: Sortino, Maximiliano AndrĂ©s. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Departamento de QuĂmica OrgĂĄnica. Ărea Farmacognosia; ArgentinaFil: Salomon, Claudio Javier. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y Farmaceuticas. Departamento de Farmacia; ArgentinaFil: Lamas, Maria Celina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y Farmaceuticas. Departamento de Farmacia; ArgentinaFil: Leonardi, DarĂo. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y Farmaceuticas. Departamento de Farmacia; Argentin
Development and Evaluation of Buccal Films Based on Chitosan for the Potential Treatment of Oral Candidiasis
In this work, chitosan films were prepared by a casting/solvent evaporation methodology using pectin or hydroxypropylmethyl cellulose to form polymeric matrices. Miconazole nitrate, as a model drug, was loaded into such formulations. These polymeric films were characterized in terms of mechanical properties, adhesiveness, and swelling as well as drug release. Besides, the morphology of raw materials and films was investigated by scanning electron microscopy; interactions between polymers were analyzed by infrared spectroscopy and drug crystallinity studied by differential scanning calorimetry and X-ray diffraction. In addition, antifungal activity against cultures of the five most important fungal opportunistic pathogens belonging to Candida genus was investigated. Chitosan:hydroxypropylmethyl cellulose films were found to be the most appropriate formulations in terms of folding endurance, mechanical properties, and adhesiveness. Also, an improvement in the dissolution rate of miconazole nitrate from the films up to 90% compared to the non-loaded drug was observed. The in vitro antifungal activity showed a significant activity of the model drug when it is loaded into chitosan films. These findings suggest that chitosan-based films are a promising approach to deliver miconazole nitrate for the treatment of candidiasis.Fil: Tejada Jacob, Guillermo Ivan. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; ArgentinaFil: Barrera, MarĂa Gabriela. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas; ArgentinaFil: Piccirilli, Gisela Noemi. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; ArgentinaFil: Sortino, Maximiliano AndrĂ©s. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Frattini, Agustin Lujan. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas; ArgentinaFil: Salomon, Claudio Javier. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; ArgentinaFil: Lamas, Maria Celina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; ArgentinaFil: Leonardi, DarĂo. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de QuĂmica Rosario. Universidad Nacional de Rosario. Facultad de Ciencias BioquĂmicas y FarmacĂ©uticas. Instituto de QuĂmica Rosario; Argentin