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Benznidazole self-emulsifying delivery system: A novel alternative dosage form for Chagas disease treatment
Ana Lia Mazzeti1, Liliam Teixeira Oliveira1, Karolina R Gonçalves2
1Laboratório de Doenças Parasitárias, Escola de Medicina & Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Universitário Morro do Cruzeiro, Ouro Preto, MG, 35400-000, Brazil; Laboratório de Desenvolvimento Galênico e Nanotecnologia, Escola de Farmácia, Universidade Federal de Ouro Preto, Campus Universitário Morro do Cruzeiro, Ouro Preto, MG, 35400-000, Brazil.
Insights
A new liquid formulation of Benznidazole (BZ) using Self-Emulsifying Drug Delivery Systems (SEDDS) offers a safe and effective alternative to tablets for treating Chagas disease in children. This BZ-SEDDS formulation maintains the drug's potency and efficacy, providing dosing flexibility for pediatric patients.
Area of Science:
- Pharmaceutical Sciences
- Parasitology
- Toxicology
Background:
- Chagas disease treatment relies on Benznidazole (BZ) tablets, posing challenges for pediatric administration.
- A liquid formulation of BZ is needed for improved oral delivery, especially for newborns.
- Self-Emulsifying Drug Delivery Systems (SEDDS) can enhance the bioavailability of poorly soluble drugs like BZ.
Purpose of the Study:
- To develop a liquid Benznidazole-SEDDS formulation as an alternative to BZ tablets.
- To evaluate the in vitro cytotoxicity and in vivo efficacy of the BZ-SEDDS formulation.
- To assess the safety profile of BZ-SEDDS in experimental models.
Main Methods:
- Development and optimization of a liquid BZ-SEDDS formulation.
- In vitro cytotoxicity assessment using H9c2, HepG2, and Caco2 cell lines.
- In vitro trypanocidal activity testing against Trypanosoma cruzi in H9c2 cells.
- In vivo efficacy study in a mouse model of acute Chagas disease.
- In vivo toxicity evaluation in treated animals.
Main Results:
- The optimized BZ-SEDDS formulation (25 mg/ml BZ) showed no cytotoxicity in host cell lines at 25 μM.
- BZ-SEDDS demonstrated comparable in vitro trypanocidal activity to free BZ (IC50: 1.29 ± 0.01 μM vs 2.10 ± 0.41 μM).
- Both free BZ and BZ-SEDDS achieved a 57% cure rate in infected mice with no additional in vivo toxicity observed.
Conclusions:
- Benznidazole-SEDDS is a viable liquid formulation alternative to BZ tablets for Chagas disease treatment.
- The SEDDS formulation preserves the efficacy, potency, and safety of Benznidazole.
- BZ-SEDDS offers practical advantages, including dosing flexibility, for treating pediatric patients, particularly newborns.
Abstract:
Benznidazole (BZ) tablets are a unique form of treatment available for treating Chagas disease. Development of a liquid formulation containing BZ easy to administer orally for the treatment of paediatric patients, particularly for newborns is urgently required, with the same efficacy, safety and suitable biopharmaceutical properties as BZ tablets. Self-emulsifying drug delivery systems (SEDDS) may improve bioavailability of drugs such as BZ, which have poor water solubility and low permeability. In this context, the aim of this work was to develop a liquid BZ-SEDDS formulation as an alternative to tablets and to evaluate its cytotoxicity in different host cell lines and its efficacy in experimental Trypanosoma cruzi infection in mice. The optimized SEDDS formulation (25 mg/ml of BZ) induced no cytotoxicity in H9c2, HepG2 and Caco2 cells in vitro at 25 μM level. BZ-SEDDS and free-BZ showed similar in vitro trypanocidal activity in H9c2 cells infected by T. cruzi Y strain, with IC50 values of 2.10 ± 0.41 μM and 1.29 ± 0.01 μM for BZ and BZ-SEDDS, respectively. A follow up of efficacy in an acute model of infected mice resulted in the same percentage of cure (57%) for both free-BZ and BZ-SEDDS- groups according to established parameters. Furthermore, no additional in vivo toxicity was observed in animals treated with BZ-SEDDS. Taken together, in vitro and in vivo data of BZ-SEDDS showed that the incorporation of BZ into SEDDS does not alter its potency, efficacy and safety. Thus, BZ-SEDDS can be a more practical and personalized orally administered liquid dosage form compared to suspension of crushed BZ-tablets to treat newborn and young children by emulsifying SEDDS in different aqueous liquids with advantage of dosing flexibility.
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