Novel sugared chewable hydrogels containing benznidazole for improve pediatric treatment of chagas' disease.

GARCÍA, MC.; SANCHEZ, MF.; MANZO, RH.; JIMENEZ KAIRUZ, AF.

Rósario

Congreso; 2ra. Reunión Internacional de Ciencias Farmacéuticoas RICiFa 2012.; 2012

Universidad Nacional de Rosario

Introduction Chagas disease is a parasitic infection caused by the flagellate protozoan Trypanosoma cruzi , and considered by WHO as a “neglected disease” . It is an important public health problem in South America and an emerging disease in Europe and North America. Benznidazole (BZN) is an active compound with significant trypanocidal activity in the acute and early chronic phases , . It is recently available as in our country in 50 and 100 mg tablets. Currently, the available solid dosage form is usually fractionated by hand to be used in newborns and children. This situation may result in some unwanted consequences, such as improper dosages and further risks of developing side-effects. In this context, this work focuses on the development and in vitro evaluation of BNZ formulations containing pediatric dose under Sugared Chewable Hydrogel (SCH) form, with taste masked and rapid drug dissolution, in order to improve pediatric Chagas´ disease pharmacotherapy. Materials and Methods BZN was extracted and purified from commercial tablets (Radanil®, 100 mg of BZN, Roche, Arg.). All GRAS (Generally Recognized As Safe) excipients as gelling agent, cosolvents, natural and artificial sweeteners, colorants, flavors and flavor enhancers were selected. Three batches of 40 units of SCH containing 50 mg BZN were prepared under constant stirring and heating at 90°C. BZN was dispersed in appropriate volume of PEG400/PEG4000/sorbitol/oleic acid blend. On other hand, gelatin was slowly dispersed in appropriate volume of high fructose syrup/water blend. This dispersion was incorporated slowly on the first one. Finally, artificial sweeteners, flavor, flavor enhancers and coloring were added, poured into mold and left to cool at room temperature for 24 h. Uniformity of weight and content, optical microscopy, rheological determinations and dissolution assays (900 mL HCl 0.1 N, paddle at 75 rpm and 37±0.5 °C), from whole and crushed SCH, were performed. Commercial tablets of Radanil®, BZN 100 mg were used as reference. Moreover, preliminary stability study was carried out on SCH stored at room temperature for 30 days. Results After preformulation studies (data not shown) was selected the SCH formulation with optimal organoleptic properties (taste palatability and visual appearance), plasticity, chewiness, uniformity and ease of stripping from molds. Acceptable weight uniformity (1.513±0.006) g and content uniformity (50.7±0.4) mg BZN were measured in compliance with pharmacopeial especifications. From dissolution studies, rapid dissolution rates of BZN (Q85% < 30 min) and not significant differences between whole and crushed SCH were observed. Microscopic observations of cross section in the middle and lower portion from SCH, showed the presence of crystallized BZN uniformly distributed. In the linear viscoelastic region, a predominant storage moduli (G’) was observed as expected for hydrogel consistency; however the viscous behavior were more sensitive to increasing stress. Stability studies showed that at least 99% of the initial BZN concentration remained throughout the 30-day. Furthermore, rheological behavior, weight uniformity, color, odor and flavor remained without sensible changes. Discussion/Conclusion A new alternative for the treatment of Chagas’ disease was developed in the form of SCH containing 50 mg BZN, through a simple and robust method, with improved pharmacotechnical and biopharmaceutical behaviors when compared with available commercial tablets. The advantage of SCH for pediatric administration is to avoid manually fragment and disperse commercial tablets, which can always lead to dosing errors. Furthermore, an efficient masked and sweet flavor was achieved after the administration, which could contribute to improve patient acceptability and treatment efficacy.