pH-SENSITIVE NANOPARTICLES FOR BENZNIDAZOLE ENTERIC RELEASE

Chagas disease is a neglected tropical illness caused by the protozoan parasite Trypanosoma cruzi. Chagas affects approximately 6-7 million of people worldwide and it is endemic in 21 Latin American countries. The primary drug used for Chagas disease treatment is benznidazole (BZ), but its application is limited due to adverse effects ranging from headaches to bone marrow depression. These side effects are associated with the fluctuations in BZ levels caused by its rapid absorption (approximately 2.93 hours in the blood) and quick elimination (resulting in low bioavailability over time). To address this issue, we propose the synthesis of an oral delivery system to enhance the efficacy and safety of BZ.
The system consists of Zein-Casein bioparticles (BP) loaded with BZ and coated with Eudragit L100-55 (BP:EU). All components are FDA-approved for oral administration in humans. BP enables sustained drug release over time, while the EU confers pH sensitivity to the material, being soluble at pH>5.5. Thus, the EU protects the BZ-loaded BP during its passage through the
stomach (pH 1.2), and starting from the duodenum (pH>5.5), it dissolves, allowing BZ release from the BP.
BP synthesis was carried out in two stages. In the first stage, BZ-loaded BP was synthesized using the antisolvent precipitation method, resulting in an average size of 230 nm. Subsequently, the coating was performed through solvent evaporation precipitation, using different BP-EU ratios (BP:EU = 1:0.5/1:1/1:2). The resulting BP:EU particles are oval-shaped with poorly defined boundaries and exhibit a wide size distribution typical of the synthesis method (Fig. 1a). The final size of BP:EU is dependent on the EU proportion, with the maximum particle diameter (D) achieved at BP:EU = 1:1 (Fig. 1b). Furthermore, the size of BP:EU changes depending on the pH, indicating the expected EU sensitivity; the size increases with higher pH values due to EU swelling in the medium. The Zeta Potential values of BP:EU indicate their stability throughout the digestive tract (Fig. 1c). The BZ release profiles in pH 1.2 and pH 6.8 (Fig. 1d) demonstrate the protective capacity of the EU in the gastric environment, where BP:EU releases less than 20% of BZ compared to the 40% released by uncoated BP. These results suggest that the system represents a potential tool for controlled and targeted BZ administration