Encapsulation Of Benznidazole In Polymeric Microparticles For The Treatment Of Chagas Disease

SEREMETA, K.; N. B. OKULIK; SALOMON, C.

San Diego

Encuentro; 2017 AAPS Annual Meeting and Exposition; 2017

American Association of Pharmaceutical Scientists (AAPS)

Purpose. Benznidazole (BNZ) is the trypanocidal drug of choice for the treatment of Chagas disease. Even though most infections occur during childhood, including newborn babies, to date, BNZ is only available in tablets, a highly inappropriate dosage form for newborns and children. In these cases, such tablets are usually fractioned by hand, which may result in improper dosage increasing the risk of side effects. The high doses of BNZ required and the long treatment (30-60 days) often leads to the development of several adverse effectsand noncompliance by the patients. BNZ is poorly soluble in water (0.4 mg/ml) which limits its oral absorption and bioavailability.Thus, the aim of this work was to evaluate whether the spray-drying process might be a proper technology for the preparation of BNZ microparticles with enhanced dissolution rate as a specific paediatric formulation for Chagas disease. Methods. 1. Preparation of BNZ-loaded microparticles (BNZ-MPs). BNZ-MPs were obtained by spray-drying. Firstly, Eudragit® RL PO, RS PO or RL PO/RS PO (1:1) (6.0 g) and BNZ (2.4 g) were dissolved in absolute ethanol (60 mL). Then, this organic phase was added to an aqueous dispersion of Sipernat® (7.5% w/v) (540 mL) and homogenized at 17,500 rpm for 5 min. The obtained suspension was fed into a Mini Spray Dryer Büchi B-290 through a two fluidnozzle. Inlet and outlet air temperature were of 130°C and 65°C, respectively. Samples were named RL, RS and RL/RS. In addition, empty MPs (without drug) were produced and used as control.2. Characterization of BNZ-MPs. 2.1. Yield, loading capacity and entrapment efficiency. The yield of each sample was calculated according to the total recoverable final weight of MPs and the total weight of BNZ. The loading capacity (%LC) and encapsulation efficiency (%EE) were obtained by dissolving an aliquot of BNZ-MPs in absolute ethanol/distilled water (97/3 v/v) and to determine the BNZ concentrationby UV-visible spectrophotometry at 324 nm.2.2. Attenuated total reflectance/Fourier transform-infrared spectroscopy (ATR/FT-IR). The samples (blank MPs, BNZ-MPs and free BNZ) were analyzed by ATR/FT-IR equipped with ATR in the range between 4000 and 600 cm−1.2.3. Dissolution studies. Dissolution studies were performed using the USP paddle method (apparatus 2). The dissolution medium (0.1 N HCl, 900 mL) was maintained at 37 ± 1 °C and 75 ± 2 rpm. The following samples were tested in triplicate: (i) MPs equivalent to 50 mg of BNZ and (ii) 50 mg of free BNZ. At regular time, aliquot of medium (4 mL) was taken and replaced by the same amount of fresh medium. The concentration of dissolved BNZ in samples was determined using a spectrophotometer at 324 nm. The dissolution profiles were compared using the dissolution efficiency at 20 min (Q20). 2.4. Stability studies. The stability at 3, 6 and 9 months of BNZ-MPs was evaluated at room temperature by means of the determination of %LC to different times and compared with %LC to zero time.ResultsSpray-drying is a rapid, cost-effective, reproducible and scalable process that can be used for the encapsulation of active compounds with relatively high efficiency and yield. In this work, BNZ was encapsulated in MPs of insoluble but permeable in digestive fluids poly(meth)acrylates, with pH-independent swelling. Regardless of the polymeric composition, %EE of MPs were high (92.6%, 90.9%and 78.8% for RL, RS and RL/RS, respectively) with %LC values of 24.35%, 23.90% and 20.71% (w/w), respectively. Differences were not statistically significant (p < 0.05) for all the formulations. Furthermore, in all samples the yield (%) was relatively high (>67%). IR spectra of the non-loaded MPs showed characteristic bands of polymers used. The BNZ-MPs showed characteristic bands of polymers and BNZ confirming that part of drug remained on the surface of MPs. Dissolution studies showed similar results in all formulations. In addition, Q20 values of BNZ-MPs were greater (93.5%, 85.5% and 82.1% for RL, RL/RS and RS, respectively) that non-encapsulated BNZ (29.6%). The high dissolution (%) of BNZ from the MPs could be due to the size reduction of the drug. In addition, part of BNZ remained on the surface of the MPs leading to a rapid dissolution in the medium of similar gastric pH. Stability studies showed that %LC did not change until, at least 9 months, in all formulations. Differences were not statistically significant (p