Hostname: page-component-586b7cd67f-r5fsc Total loading time: 0 Render date: 2024-11-26T20:46:06.709Z Has data issue: false hasContentIssue false
  • English
  • Français

In vitro studies and preclinical evaluation of benznidazole microparticles in the acute Trypanosoma cruzi murine model

Published online by Cambridge University Press:  10 December 2020

Marcela S. Rial ,
Katia P. Seremeta ,
Mónica I. Esteva ,
Jacqueline Búa ,
Claudio J. Salomon  and
Laura E. Fichera Open the ORCID record for Laura E. Fichera [Opens in a new window]
Marcela S. Rial
Affiliation:
Instituto Nacional de Parasitología Dr M. Fatala Chaben, ANLIS CG Malbrán, Ministerio de Salud, Av. Paseo Colón 568, Ciudad de Buenos Aires, Argentina
Katia P. Seremeta
Affiliation:
Departamento de Ciencias Básicas y Aplicadas, Universidad Nacional del Chaco Austral, Cte. Fernández 755, 3700, Pcia. Roque Sáenz Peña, Chaco, Argentina Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Mónica I. Esteva
Affiliation:
Instituto Nacional de Parasitología Dr M. Fatala Chaben, ANLIS CG Malbrán, Ministerio de Salud, Av. Paseo Colón 568, Ciudad de Buenos Aires, Argentina
Jacqueline Búa
Affiliation:
Instituto Nacional de Parasitología Dr M. Fatala Chaben, ANLIS CG Malbrán, Ministerio de Salud, Av. Paseo Colón 568, Ciudad de Buenos Aires, Argentina Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Claudio J. Salomon*
Affiliation:
Instituto de Química Rosario, Consejo Nacional de Investigaciones Científicas y Técnicas (IQUIR-CONICET), Suipacha 531, 2000, Rosario, Argentina Área Técnica Farmacéutica, Departamento de Farmacia, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina
Laura E. Fichera*
Affiliation:
Instituto Nacional de Parasitología Dr M. Fatala Chaben, ANLIS CG Malbrán, Ministerio de Salud, Av. Paseo Colón 568, Ciudad de Buenos Aires, Argentina Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
*
Author for correspondence: Laura E. Fichera, E-mail: [email protected]; Claudio J. Salomon, E-mail: [email protected]
Author for correspondence: Laura E. Fichera, E-mail: [email protected]; Claudio J. Salomon, E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Chagas disease is a serious parasitic infection caused by Trypanosoma cruzi. Unfortunately, the current chemotherapeutic tools are not enough to combat the infection. The aim of this study was to evaluate the trypanocidal activity of benznidazole-loaded microparticles during the acute phase of Chagas infection in an experimental murine model. Microparticles were prepared by spray-drying using copolymers derived from esters of acrylic and methacrylic acids as carriers. Dissolution efficiency of the formulations was up to 3.80-fold greater than that of raw benznidazole. Stability assay showed no significant difference (P > 0.05) in the loading capacity of microparticles for 3 years. Cell cultures showed no visible morphological changes or destabilization of the cell membrane nor haemolysis was observed in defibrinated human blood after microparticles treatment. Mice with acute lethal infection survived 100% after 30 days of treatment with benznidazole microparticles (50 mg kg−1 day−1). Furthermore, no detectable parasite load measured by quantitative polymerase chain reaction and lower levels of T. cruzi-specific antibodies by enzyme-linked immunosorbent assay were found in those mice. A significant decrease in the inflammation of heart tissue after treatment with these microparticles was observed, in comparison with the inflammatory damage observed in both infected mice treated with raw benznidazole and untreated infected mice. Therefore, these polymeric formulations are an attractive approach to treat Chagas disease.

Keywords

BenznidazoleChagas diseaseEudragit®experimental infectionmicroparticlesspray-drying
Type
Research Article
Information
Parasitology , Volume 148 , Issue 5 , April 2021 , pp. 566 - 575
Check for updates
Copyright
Copyright © The Author(s), 2020. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Abuzar, SM, Hyun, SM, Kim, JH, Park, HJ, Kim, MS, Park, JS and Hwang, SJ (2018) Enhancing the solubility and bioavailability of poorly water-soluble drugs using supercritical antisolvent (SAS) process. International Journal of Pharmaceutics 538, 1–13.CrossRefGoogle ScholarPubMed
Al-Khattawi, A, Bayly, A, Phillips, A and Wilson, D (2018) The design and scale-up of spray dried particle delivery systems. Expert Opinion on Drug Delivery 15, 47–63.CrossRefGoogle ScholarPubMed
Altcheh, J, Moscatelli, J, Moroni, S, Garcia-Bournissen, F and Freilij, H (2011) Adverse events after the use of benznidazole in infants and children with Chagas disease. Pediatrics 127, e212–e218.CrossRefGoogle ScholarPubMed
Apt, W (2010) Current and developing therapeutic agents in the treatment of Chagas disease. Drug Design, Development and Therapy 4, 243–253.CrossRefGoogle ScholarPubMed
Apu, AS, Pathan, AH, Shrestha, D, Kibria, G and Jalil, R (2009) Investigation of in vitro release kinetics of carbamazepine from Eudragit® RS PO and RL P matrix tablets. Tropical Journal of Pharmaceutical Research 8, 145–152.CrossRefGoogle Scholar
Barrera, MG, Tejada, G, Leonardi, D, Lamas, MC and Salomon, CJ (2020) A novel prototype device for microencapsulation of benznidazole: in vitro/in vivo studies. AAPS PharmSciTech 21, 112.CrossRefGoogle ScholarPubMed
Bonney, KM (2014) Chagas disease in the 21st century: a public health success or an emerging threat? Parasite 21, 1–10.CrossRefGoogle ScholarPubMed
Broeckx, G, Vandenheuvel, D, Henkens, T, Kiekens, S, van den Broek, MFL, Lebeer, S and Kiekens, F (2017) Enhancing the viability of Lactobacillus rhamnosus GG after spray drying and during storage. International Journal of Pharmaceutics 534, 35–41.CrossRefGoogle ScholarPubMed
Bua, J, Volta, BJ, Perrone, AE, Scollo, K, Velázquez, EB, Ruiz, AM, De Rissio, AM and Cardoni, RL (2013) How to improve the early diagnosis of Trypanosoma cruzi infection: relationship between validated conventional diagnosis and quantitative DNA amplification in congenitally infected children. PLoS Neglected Tropical Diseases 7, e2476.CrossRefGoogle ScholarPubMed
Buckley, ST, Frank, KJ, Fricker, G and Brandl, M (2013) Biopharmaceutical classification of poorly soluble drugs with respect to ‘enabling formulations’. European Journal of Pharmaceutical Sciences 50, 8–16.CrossRefGoogle Scholar
Cardoso, CS, Ribeiro, ALP, Oliveira, CDL, Oliveira, LC, Ferreira, AM, Bierrenbach, AL, Silva, JLP, Colosimo, EA, Ferreira, JE, Lee, T-H, Busch, MP, Reingold, AL and Sabino, EC (2018) Beneficial effects of benznidazole in Chagas disease: NIH SaMi-Trop cohort study. PLoS Neglected Tropical Diseases 12, e0006814.CrossRefGoogle ScholarPubMed
Cilurzo, F, Selmina, F, Minghettia, P, Gennaria, CGM, Demartin, F and Montanaria, L (2008) Characterization and physical stability of fast-dissolving microparticles containing nifedipine. European Journal of Pharmaceutics and Biopharmaceutics 68, 579–588.CrossRefGoogle ScholarPubMed
Cortesi, R, Lahm Ajanji, SC, Sivieri, E, Manservigi, M, Fundueanu, G, Menegatti, E and Esposito, E (2007) Eudragit® microparticles as a possible tool for ophthalmic administration of acyclovir. Journal of Microencapsulation 24, 445–456.CrossRefGoogle Scholar
Crespillo-Andújar, C, Chamorro-Tojeiro, S, Norman, F, Monge-Maillo, B, López-Vélez, R and Pérez-Molina, JA (2018) Toxicity of nifurtimox as second-line treatment after benznidazole intolerance in patients with chronic Chagas disease: when available options fail. Clinical Microbiology and Infection 24:1344.e1–1344.e4.CrossRefGoogle ScholarPubMed
Davis, M and Walker, G (2018) Recent strategies in spray drying for the enhanced bioavailability of poorly water-soluble drugs. Journal of Controlled Release 269, 110–127.CrossRefGoogle ScholarPubMed
Del Moral Sanchez, JM, Gonzalez-Alvarez, I, Cerda-Revert, A, Gonzalez-Alvarez, M, Navarro-Ruiz, A, Almidon, GL and Bermejo, M (2018) Biopharmaceutical optimization in neglected diseases for paediatric patients by applying the provisional paediatric biopharmaceutical classification system. British Journal of Clinical Pharmacology 84, 2231–2241.CrossRefGoogle ScholarPubMed
Dixit, K, Athawale, RB and Singh, S (2015) Quality control of residual solvent content in polymeric microparticles. Journal of Microencapsulation, Micro and Nano Carriers 32, 107–122.CrossRefGoogle ScholarPubMed
Duffy, T, Bisio, M, Altcheh, J, Burgos, JM, Diez, M, Levin, MJ, Favaloro, RR, Freilij, H and Schijman, AG (2009) Accurate real-time PCR strategy for monitoring bloodstream parasitic loads in Chagas disease patients. PLoS Neglected Tropical Diseases 3, e419.CrossRefGoogle ScholarPubMed
Emami, F, Vatanara, A, Park, EJ and Na, DH (2018) Drying technologies for the stability and bioavailability of biopharmaceuticals. Pharmaceutics 10, E131.CrossRefGoogle ScholarPubMed
Ferraz, LRM, Alves, AÉG, Nascimento, DDSDS, Amariz, IAE, Ferreira, AS, Costa, SPM, Rolim, LA, Lima, ÁAN and Rolim Neto, PJ (2018) Technological innovation strategies for the specific treatment of Chagas disease based on benznidazole. Acta Tropica 185, 127–132.CrossRefGoogle ScholarPubMed
Grosso, NL, Bua, J, Perrone, AE, Gonzalez, MN, Bustos, PL, Postan, M and Fichera, LE (2010) Trypanosoma cruzi: biological characterization of an isolate from an endemic area and its susceptibility to conventional drugs. Experimental Parasitology 126, 239–244.CrossRefGoogle ScholarPubMed
Grosso, NL, Alarcon, ML, Bua, J, Laucella, SA, Riarte, A and Fichera, LE (2013) Combined treatment with benznidazole and allopurinol in mice infected with a virulent Trypanosoma cruzi isolate from Nicaragua. Parasitology 140, 1225–1233.CrossRefGoogle ScholarPubMed
Gupta, S and Garg, NJ (2010) Prophylactic efficacy of TcVac2 against Trypanosoma cruzi in mice. PLoS Neglected Tropical Diseases 4, e797.CrossRefGoogle ScholarPubMed
Haque, S, Boyd, BJ, McIntosh, MP, Pouton, CW, Kaminskas, LM and Whittaker, M (2018) Suggested procedures for the reproducible synthesis of poly(d,l-lactide-co-glycolide) nanoparticles using the emulsification solvent diffusion platform. Current Nanoscience 14, 448–453.CrossRefGoogle ScholarPubMed
Higashi, K, Hayashi, H, Yamamoto, K and Moribe, K (2015) The effect of drug and EUDRAGIT® S 100 miscibility in solid dispersions on the drug and polymer dissolution rate. International Journal of Pharmaceutics 494, 9–16.CrossRefGoogle ScholarPubMed
Kemp, IC, Hartwig, T, Herdman, R, Hamilton, P, Bisten, A and Bermingham, S (2016) Spray drying with a two-fluid nozzle to produce fine particles: atomization, scale-up, and modeling. Drying Technology 34, 1243–1252.CrossRefGoogle Scholar
Kratz, JM, Garcia Bournissen, F, Forsyth, CJ and Sosa-Estani, S (2018) Clinical and pharmacological profile of benznidazole for treatment of Chagas disease. Expert Review of Clinical Pharmacology 11, 943–957.CrossRefGoogle ScholarPubMed
Lengyel, M, Kállai-Szabó, N, Antal, V, Laki, AJ and Antal, I (2019) Microparticles, microspheres, and microcapsules for advanced drug delivery. Scientia Pharmaceutica 87, 20.CrossRefGoogle Scholar
Leonardi, D, Salomón, CJ, Lamas, MC and Olivieri, AC (2009) Development of novel formulations for Chagas’ disease: optimization of benznidazole chitosan microparticles based on artificial neural networks. International Journal of Pharmaceutics 367, 140–147.CrossRefGoogle ScholarPubMed
Leonardi, D, Bombardiere, ME and Salomon, CJ (2013) Effects of benznidazole: cyclodextrin complexes on the drug bioavailability upon oral administration to rats. International Journal of Biological Macromolecules 62, 543–548.CrossRefGoogle ScholarPubMed
Li, M, Rouaud, O and Poncelet, D (2008) Microencapsulation by solvent evaporation: state of the art for process engineering approaches. International Journal of Pharmaceutics 363, 26–39.CrossRefGoogle ScholarPubMed
Lima, AAN, Soares-Sobrinho, JL, Silva, JL, Hernandes, MZ, Rolim, LA and Rolim-Neto, PJ (2011) The use of solid dispersion systems in hydrophilic carriers to increase benznidazole solubility. Pharmaceutical Technology 100, 2443–2451.Google ScholarPubMed
Liu, F, Park, JY, Zhang, Y, Conwell, C, Liu, Y, Bathula, SR and Huang, L (2010) Targeted cancer therapy with novel high drug-loading nanocrystals. Journal of Pharmaceutical Sciences 99, 3542–3551.CrossRefGoogle ScholarPubMed
Maximiano, FP, de Paula, LM, Figueiredo, VP, de Andrade, IM, Talvani, A, Sá-Barreto, LC, Bahia, MT and Cunha-Filho, MS (2011) Benznidazole microcrystal preparation by solvent change precipitation and in vivo evaluation in the treatment of Chagas disease. European Journal of Pharmaceutics and Biopharmaceutics 78, 377–384.CrossRefGoogle ScholarPubMed
Maya, JD, Cassels, BK, Iturriaga-Vásquez, P, Ferreira, J, Faúndez, M, Galanti, N, Ferreira, A and Morello, A (2007) Mode of action of natural and synthetic drugs against Trypanosoma cruzi and their interaction with the mammalian host. Comparative Biochemistry and Physiology – Part A: Molecular & Integrative Physiology Special Issues 146, 601–620.CrossRefGoogle ScholarPubMed
Meymandi, S, Hernandez, S, Park, S, Sanchez, DR and Forsyth, C (2018) Treatment of Chagas disease in the United States. Current Treatment Options in Infectious Diseases 10, 373–388.CrossRefGoogle ScholarPubMed
Morillo, CA, Marin-Neto, JA, Avezum, A, Sosa-Estani, S, Rassi, A, Rosas, F, Villena, E, Quiroz, R, Bonilla, R, Britto, C, Guhl, F, Velazquez, E, Bonilla, L, Meeks, B, Rao-Melacini, P, Pogue, J, Mattos, A, Lazdins, J, Rassi, A, Connolly, SJ and Yusuf, S and BENEFIT Investigators (2015) Randomized trial of benznidazole for chronic Chagas’ cardiomyopathy. The New England Journal of Medicine 373, 1295–1306.CrossRefGoogle ScholarPubMed
Paulo, F and Santos, L (2017) Design of experiments for microencapsulation applications: a review. Materials Science and Engineering C: Materials for Biological Applications 77, 1327–1340.CrossRefGoogle ScholarPubMed
Pérez-Molina, JA, Pérez-Ayala, A, Moreno, S, Fernández-González, MC, Zamora, J and López-Velez, R (2009) Use of benznidazole to treat chronic Chagas’ disease: a systematic review with a meta-analysis. Journal of Antimicrobial Chemotherapy 64, 1139–1147.CrossRefGoogle ScholarPubMed
Piccirilli, GN, García, A, Leonardi, D, Mamprin, ME, Bolmaro, RE, Salomón, CJ and Lamas, MC (2014) Chitosan microparticles: influence of the gelation process on the release profile and oral bioavailability of albendazole, a class II compound. Drug Development and Industrial Pharmacy 40, 1476–1482.CrossRefGoogle ScholarPubMed
Poozesh, S and Bilgili, E (2019) Scale-up of pharmaceutical spray drying using scale-up rules: a review. International Journal of Pharmaceutics 562, 271–292.CrossRefGoogle ScholarPubMed
Quijia Quezada, C, Azevedo, CS, Charneau, S, Santana, JM, Chorilli, M, Carneiro, MB and Bastos, IMD (2019) Advances in nanocarriers as drug delivery systems in Chagas disease. International Journal of Nanomedicine 14, 6407–6424.CrossRefGoogle ScholarPubMed
Rial, MS, Scalise, ML, Arrúa, EC, Esteva, MI, Salomon, CJ and Fichera, LE (2017) Elucidating the impact of low doses of nano-formulated benznidazole in acute experimental Chagas disease. PLoS Neglected Tropical Diseases 11, e0006119.CrossRefGoogle ScholarPubMed
Rial, MS, Scalise, ML, López Alarcón, M, Esteva, MI, Búa, J, Benatar, AF, Prado, NG, Riarte, AR and Fichera, LE (2019) Experimental combination therapy using low doses of benznidazole and allopurinol in mouse models of Trypanosoma cruzi chronic infection. Parasitology 146, 305–313.CrossRefGoogle ScholarPubMed
Rial, MS, Arrua, EC, Natale, MA, Bua, J, Esteva, MI, Prado, NG, Laucella, SA, Salomon, CJ and Fichera, LE (2020) Efficacy of continuous versus intermittent administration of nanoformulated benznidazole during the chronic phase of Trypanosoma cruzi Nicaragua infection in mice. Journal of Antimicrobial Chemotherapy 75, 1906–1916.CrossRefGoogle ScholarPubMed
Ribeiro, V, Dias, N, Paiva, T, Hagström-Bex, L, Nitz, N, Pratesi, R and Hecht, M (2020) Current trends in the pharmacological management of Chagas disease. International Journal for Parasitology: Drugs and Drug Resistance 12, 7–17.Google ScholarPubMed
Salomon, CJ (2012) First century of Chagas’ disease: an overview on novel approaches to nifurtimox and benznidazole delivery systems. Journal of Pharmaceutical Sciences 101, 888–894.CrossRefGoogle ScholarPubMed
Sanchez-Vazquez, B, Lee, JB, Strimaite, M, Buanz, A, Bailey, R, Gershkovich, P, Pasparakisa, P and Williams, GR (2019) Solid lipid nanoparticles self-assembled from spray dried microparticles. International Journal of Pharmaceutics 572, 118784.CrossRefGoogle ScholarPubMed
Scalise, ML, Arrúa, EC, Rial, MS, Esteva, MI, Salomon, CJ and Fichera, LE (2016) Promising efficacy of benznidazole nanoparticles in acute Trypanosoma cruzi murine model: in-vitro and in-vivo studies. The American Journal of Tropical Medicine and Hygiene 95, 388–393.CrossRefGoogle ScholarPubMed
Seremeta, KP, Arrúa, EC, Okulik, NB and Salomon, CJ (2019) Development and characterization of benznidazole nano- and microparticles: a new tool for pediatric treatment of Chagas disease? Colloids and Surfaces B: Biointerfaces 177, 169–177.CrossRefGoogle ScholarPubMed
Sguassero, Y, Cuesta, CB, Roberts, KN, Hicks, E, Comandé, D, Ciapponi, A and Sosa-Estani, S (2015) Course of chronic Trypanosoma cruzi infection after treatment based on parasitological and serological tests: a systematic review of follow-up studies. PLoS ONE 10, e0139363.CrossRefGoogle ScholarPubMed
Shim, H and Sah, H (2020) Qualification of non-halogenated organic solvents applied to microsphere manufacturing process. Pharmaceutics 12, 425.CrossRefGoogle ScholarPubMed
Singh, A and Van den Mooter, G (2016) Spray drying formulation of amorphous solid dispersions. Advanced Drug Delivery Reviews 100, 27–50.CrossRefGoogle ScholarPubMed
Sosa Estani, S, Segura, EL, Ruiz, AM, Velazquez, E, Porcel, BM and Yampotis, C (1998) Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas’ disease. The American Journal of Tropical Medicine and Hygiene 59, 526–529.CrossRefGoogle ScholarPubMed
Sosnik, A and Seremeta, KP (2015) Advantages and challenges of the spray-drying technology for the production of pure drug particles and drug-loaded polymeric carriers. Advances in Colloid and Interface Science 223, 40–54.CrossRefGoogle ScholarPubMed
Strauss, M, Lo Presti, S, Bazán, PC, Baez, A, Fauro, R, Esteves, B, Sanchez Negrete, O, Cremonezzi, D, Paglini-Oliva, PA and Rivarola, HW (2013) Clomipramine and benznidazole association for the treatment of acute experimental Trypanosoma cruzi infection. Parasitology International 62, 293–299.CrossRefGoogle ScholarPubMed
Tanowitz, HB, Machado, FS, Spray, DC, Friedman, JM, Weiss, OS, Lora, JN, Nagajyothi, J, Moraes, DN, Garg, NJ, Nunes, MC and Ribeiro, AL (2015) Developments in the management of Chagas cardiomyopathy. Expert Review of Cardiovascular Therapy 13, 1393–1409.CrossRefGoogle ScholarPubMed
Thakral, S, Thakral, NK and Majumdar, DK (2013) Eudragit®: a technology evaluation. Expert Opinion on Drug Delivery 10, 131–149.CrossRefGoogle Scholar
Vinuesa, T, Herráez, R, Oliver, L, Elizondo, E, Acarregui, A, Esquisabel, A, Pedraz, JL, Ventosa, N, Veciana, J and Viñas, M (2017) Benznidazole nanoformulates: a chance to improve therapeutics for Chagas disease. The American Journal of Tropical Medicine and Hygiene 97, 1469–1476.CrossRefGoogle ScholarPubMed
Viotti, R, Vigliano, C, Lococo, B, Alvarez, MG, Petti, M, Bertocchi, G and Armenti, A (2009) Side effects of benznidazole as treatment in chronic Chagas disease: fears and realities. Expert Review of Anti-infective Therapy 7, 157–163.CrossRefGoogle ScholarPubMed
World Health Organization (2020) Chagas disease (also known as American trypanosomiasis). Available at https://www.who.int/en/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis).Google Scholar
Wu, L, Zhang, J and Watanabe, W (2011) Physical and chemical stability of drug nanoparticles. Advanced Drug Delivery Reviews 63, 456–469.CrossRefGoogle ScholarPubMed
Ziaee, A, Albadarin, AB, Padrela, L, Femmer, T, O'Reilly, E and Walker, G (2019) Spray drying of pharmaceuticals and biopharmaceuticals: critical parameters and experimental process optimization approaches. European Journal of Pharmaceutical Sciences 127, 300–318.CrossRefGoogle ScholarPubMed
Supplementary material: File

Rial et al. supplementary material

Tables S1-S2

Download Rial et al. supplementary material(File)
File 14.3 KB