UNITEFA   23945
UNIDAD DE INVESTIGACION Y DESARROLLO EN TECNOLOGIA FARMACEUTICA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Controlled release microparticles of benznidazol based on interpolyelectrolyte complexes.
Autor/es:
GARCÍA, MC.; MANZO, RH.; JIMENEZ KAIRUZ, AF.
Lugar:
Porto Gallinas
Reunión:
Simposio; XIV Latin American Symposium on Polymers, SLAP 2014.; 2014
Institución organizadora:
Asociación Brasileira de Polímeros
Resumen:
1 INTRODUCTION Chagas disease, or American trypanosomiasis, is a vector-borne disease listed by the World Health Organization (WHO) as a ?neglected or forgotten disease?. It is endemic in 21 countries in Latin America, affecting over 20 million people , . Currently, we only have two useful drugs for Chagas? treatment: nifurtimox and benznidazole (BNZ), but the availability of data is limited. Nifurtimox (Bayer 2502, Lampit®) [5-nitrofuran (3-methyl-4-(5´-nitrofurfurylideneamine)tetrahydro-4H-1,4-tiazine-1,1-dioxide(Bayer 2502)] was approved for use in 1965 and it production is now discontinued. Moreover, BNZ (RO7-1051, Rochagan®, Radanil®) [2-nitroimidazole (N-benzyl-2-nitroimidazole acetamide], was authorized for marketing in 1972. In general the use of BNZ in the acute phase of Chagas disease, with proven efficacy ≥ 80% , but the indication of this drug in chronic phase is still controversial due to the high intolerance, toxicity, frequency of adverse reactions and/or resistance, which affects between 4 and 30 % of treated individuals , , , . Evidence suggests that the side effects of BNZ are characterized by skin reactions (pruritic macular rash), polyneuropathy, gastrointestinal disorders (nausea, diarrhea), febrile syndrome, headache and dizziness. However, given the variability of the results, the frequency of their occurrence has not been established with certainty. The unfavorable physicochemical properties and high incidence of adverse effects associated with the use of BNZ, limit the effectiveness and compliance of treatment. Acidic or basic PE selected to develop microparticles are widely used in the pharmaceutical industry for different purposes, but their properties as drug carriers have not been completely studied yet. The Eudragit´s polymers are approved for pharmaceutical use, and they are included in the GRAS (Generally Recognized As Safe) list of Food and Drug Administration. In this context, the aim of this work was to obtain functionalized microparticles based on interpolyelectrolyte complexes (IPEC) for controlled release of BZ. 2 MATERIALS AND METHODS 2.2 Materials EuL, EuS and EuLD (mean MW = 135,000), and EuE (mean MW = 150,000) were gently supplied by Etilpharma (Bs. As., Arg.). AA and CHI (Sigma Aldrich, USA); and BZ (Maprimed, Arg.) were used. The proportions of ionizable groups of the two PE were previously determined by potentiometric titrations . 2.2 Preparation of interpolyelectrolyte complexes Two series of IPEC microparticles were prepared by wet granulation process, based on natural polyelectrolytes (PE) by acid-base interaction with Alginic Acid and Chitosan, and other based on synthetic PE, by acid-base interaction between Eudragit EPO with different anionic Eudragit L100, S100, L10055 and FS. Figure 1 is the representation of complete IPEC preparation. An appropriate amount of two PEs and BZ, in solid state, were mixed in a mortar. An appropriate proportion of solvent, water (2.0±0.4 ml/g of solids) or water:ethanol 1:1 (1.7±0.5 ml/g of solids) were added as reaction media and mixed up to obtain a homogeneous mass. The blends of IPEC loaded with BZ were dried to constant weight at 40°C. The microparticles of IPEC-BZ were prepared by wet granulation process, using water as blending agents in a proportion of 43±3% w/w H2O/IPEC and then granulated by analytical sieves. The microparticles were dried at to constant weight at 40°C 2.2 Rheology studies The mechanical characterization of IPEC microparticles was evaluated by measured of bulk density and tap density (δ), angle of repose (α). In addition Compressibility index (CI) and Hausner index (HI) were calculated according to pharmacopoeia specification. 2.2 Fluids sorption and drug release studies The fluid sorption of IPEC microparticles was performed using a modified Elsin apparatus. Drug release studies were performed in Apparatus 1-?Basket? USP-Dissolution testing using 900 ml of two bio-relevant fluids (pH 1.2, 0.1M HCl soln. and pH 6.8, Phosphate buffer soln.) according to extended release testing of pharmacopeia specifications. The IPEC-BZ microparticles were formulated in gelatin capsules. The release profiles processed statistically and by mathematical kinetic models (Peppas, Higuchi and zero order) allowed inferring release mechanisms. 3 RESULTS AND DISCUSSION The functionalized microparticles of IPEC loaded with BNZ, under the form of solid dispersions, were obtained using a simple and reproducible method. The production yields of IPEC-BZ microparticles were > 93%, and acceptable dose uniformity of BZ. The microparticles with particle size between 600-850μm were selected to perform the fluid sorption and drug release studies. Rheological studies showed optimal physicomechanical properties for formulation into capsules. High δbulk, IC values below 15 and α below 40° were indicating good flow behaviors of microparticles to formulate in capsule pharmaceutical forms. Figures 3a and 3b show the dissolution profiles of IPEC microparticles obtained in two different acid-base interaction media: water or hydroalcoholic solvents, respectively. The dissolution profiles showed a high capacity for modulating the release of BNZ from these, ranging from very slow and controlled (Q120min ≤ 40%) to very fast (Q15min> 85%) according to the composition of IPEC. The release rate of polymethacrylates complexes obtained in water followed the sequence EuL > EuS >> EuLD. A more controlled release was observed in the sequence of complexes obtained using hydroalcocholic solvent (EuS > EuL ≈ EuLD). In general, the change of pH of dissolution medium, from pH=1.2 to 6.8, produced an activation of BZ delivery from microparticles. These behaviors are related to different aqueous solubility of polymethacrylates used. The more uniform delivery properties of complexes obtained in hydroalcoholic solvent could be attributed to more hydrophobic network of dried complexes. The fluid sorption studies showed in figure 4 allowed linking these results with those obtained in release studies. In acidic medium, the sorption rate followed the sequence EuL >> EuS ≈ EuLD. On the other hand, the complexes based on natural PE not significant differences in release profiles respect the solvent used in preparation of IPEC were observed. In addition, pH-independent modified release profiles were obtained from both types of complexes. The analysis of release profiles allowed identified erosion-relaxation and swelling-diffusion as predominant release mechanisms in polymethacrilates based and natural complexes, respectively. The results obtained in this work are promising to design multiparticulate dosage forms, by formulate in a monolithic systems (as hard gelatin capsules) different composition IPEC with functionalized BZ in order to obtain multi-kinetic release profiles. This behavior could optimize the gastrointestinal BZ dissolution and relative bioavailability. 4 CONCLUSIONS Microparticulate systems were obtained in good yield by using simple, reproducible and inexpensive process, containing BNZ functionalized in IPEC systems with controlled release properties. Additional studies in vitro and in vivo are needed to confirm the efficacy and safety of these innovative pharmaceutical alternatives and their usefulness in the treatment of this "neglected disease".