Solid nanomedicines of nifurtimox and benznidazole for the oral treatment of Chagas disease

Miriam Rolon; Eustine Hanna; Celeste Vega; Cathia Coronel; Maria Auxiliadora Dea-Ayuela; Dolores R. Serrano; Aikaterini Lalatsa

doi:10.3390/pharmaceutics14091822

Solid nanomedicines of nifurtimox and benznidazole for the oral treatment of Chagas disease

Miriam Rolon, Eustine Hanna, Celeste Vega, Cathia Coronel, Maria Auxiliadora Dea-Ayuela, Dolores R. Serrano, Aikaterini Lalatsa

Strathclyde Institute Of Pharmacy And Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

40 Downloads (Pure)

Abstract

Chagas disease (CD) is a parasitic zoonosis endemic in Central and South America affecting nearly 10 million people, with 100 million people at high risk of contracting the disease. Treatment is only effective when received at the early stages of the disease and it involved two drugs (nifurtimox (NFX) and benznidazole (BNZ)). Both treatments require multiple daily administrations of high doses, suffer from variable efficacy and insufficient efficacy in chronic CD, many side effects, and a very long duration of treatment that results in poor compliance, while combined available therapies that lead to reduced duration of treatment are not available and polypharmacy reduces compliance and increases the cost further. Here we present self-nanoemulsified drug delivery systems (SNEDDS) able to produce easily scalable combined formulations of NFX and BNZ that can allow for tailoring of the dose and can be easily converted to oral solid dosage form by impregnation on mesoporous silica particles. SNEDDS demonstrated an enhanced solubilisation capacity for both drugs as demonstrated by flow-through studies and in vitro lipolysis studies. High loading of SNEDDS to Syloid 244 and 3050 silicas (2:1 w/w) allowed clinically translatable amounts of both NFX and BNZ to be loaded. Tablets prepared from NFX-BNZ combined SNEDDS loaded on Syloid 3050 silicas demonstration near complete dissolution in the flow through cell apparatus compared to NFX and BNZ commercial tablets respectively (Lampit ^® and Rochagan ^®). NFX-BNZ-SNEDDS demonstrated nanomolar efficacy in epimastigotes and amastigotes of T. cruzi with acceptable selectivity indexes and demonstrated enhanced survival and reduced parasitaemia in acute murine experimental models of CD. Thus, the results presented here illustrate the ability for an easily scalable and personalised combination oral therapy prepared from GRAS excipients, enabling treatment access worldwide for the treatment of CD.

Original language	English
Article number	1822
Number of pages	25
Journal	Pharmaceutics
Volume	14
Issue number	9
Early online date	29 Aug 2022
DOIs	https://doi.org/10.3390/pharmaceutics14091822
Publication status	Published - 29 Aug 2022

Funding

This research was funded by the Consejo Nacional de Ciencia y Tecnología (CONACYT, Paraguay) and PRONII-CONACYT (National Incentive Program to Researchers of the National Science and Technological Council) (project 14-INV-022, Paraguay), the Royal Society (RG130542), and by a University of Portsmouth, Research and Development Fund. Eustine Hanna was supported by an Erasmus+ to undertake research placements at UCM, Madrid, Spain.

Keywords

Chagas disease
trypanosomiasis
self-nanoemulsifying drug delivery systems (SNEDDS)
Nifurtimox
Benznidazole
silicon dioxide (silica)
solid self-nanoemulsifying drug delivery systems (Solid-SNEDDS)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.3390/pharmaceutics14091822Licence: CC BY 4.0

Rolon-etal-Pharmaceutics-2022-Solid-nanomedicines-of-nifurtimox-and-benznidazole-for-the-oral-treatment-of-Chagas-diseaseFinal published version, 3.94 MBLicence: CC BY 4.0

Cite this

@article{5e32ba0cf337464fb45b4fe5793ff3a3,

title = "Solid nanomedicines of nifurtimox and benznidazole for the oral treatment of Chagas disease",

abstract = "Chagas disease (CD) is a parasitic zoonosis endemic in Central and South America affecting nearly 10 million people, with 100 million people at high risk of contracting the disease. Treatment is only effective when received at the early stages of the disease and it involved two drugs (nifurtimox (NFX) and benznidazole (BNZ)). Both treatments require multiple daily administrations of high doses, suffer from variable efficacy and insufficient efficacy in chronic CD, many side effects, and a very long duration of treatment that results in poor compliance, while combined available therapies that lead to reduced duration of treatment are not available and polypharmacy reduces compliance and increases the cost further. Here we present self-nanoemulsified drug delivery systems (SNEDDS) able to produce easily scalable combined formulations of NFX and BNZ that can allow for tailoring of the dose and can be easily converted to oral solid dosage form by impregnation on mesoporous silica particles. SNEDDS demonstrated an enhanced solubilisation capacity for both drugs as demonstrated by flow-through studies and in vitro lipolysis studies. High loading of SNEDDS to Syloid 244 and 3050 silicas (2:1 w/w) allowed clinically translatable amounts of both NFX and BNZ to be loaded. Tablets prepared from NFX-BNZ combined SNEDDS loaded on Syloid 3050 silicas demonstration near complete dissolution in the flow through cell apparatus compared to NFX and BNZ commercial tablets respectively (Lampit {\textregistered} and Rochagan {\textregistered}). NFX-BNZ-SNEDDS demonstrated nanomolar efficacy in epimastigotes and amastigotes of T. cruzi with acceptable selectivity indexes and demonstrated enhanced survival and reduced parasitaemia in acute murine experimental models of CD. Thus, the results presented here illustrate the ability for an easily scalable and personalised combination oral therapy prepared from GRAS excipients, enabling treatment access worldwide for the treatment of CD.",

keywords = "Chagas disease, trypanosomiasis, self-nanoemulsifying drug delivery systems (SNEDDS), Nifurtimox, Benznidazole, silicon dioxide (silica), solid self-nanoemulsifying drug delivery systems (Solid-SNEDDS)",

author = "Miriam Rolon and Eustine Hanna and Celeste Vega and Cathia Coronel and Dea-Ayuela, {Maria Auxiliadora} and Serrano, {Dolores R.} and Aikaterini Lalatsa",

year = "2022",

month = aug,

day = "29",

doi = "10.3390/pharmaceutics14091822",

language = "English",

volume = "14",

journal = "Pharmaceutics",

issn = "1999-4923",

publisher = "MDPI AG",

number = "9",

}

TY - JOUR

T1 - Solid nanomedicines of nifurtimox and benznidazole for the oral treatment of Chagas disease

AU - Rolon, Miriam

AU - Hanna, Eustine

AU - Vega, Celeste

AU - Coronel, Cathia

AU - Dea-Ayuela, Maria Auxiliadora

AU - Serrano, Dolores R.

AU - Lalatsa, Aikaterini

PY - 2022/8/29

Y1 - 2022/8/29

N2 - Chagas disease (CD) is a parasitic zoonosis endemic in Central and South America affecting nearly 10 million people, with 100 million people at high risk of contracting the disease. Treatment is only effective when received at the early stages of the disease and it involved two drugs (nifurtimox (NFX) and benznidazole (BNZ)). Both treatments require multiple daily administrations of high doses, suffer from variable efficacy and insufficient efficacy in chronic CD, many side effects, and a very long duration of treatment that results in poor compliance, while combined available therapies that lead to reduced duration of treatment are not available and polypharmacy reduces compliance and increases the cost further. Here we present self-nanoemulsified drug delivery systems (SNEDDS) able to produce easily scalable combined formulations of NFX and BNZ that can allow for tailoring of the dose and can be easily converted to oral solid dosage form by impregnation on mesoporous silica particles. SNEDDS demonstrated an enhanced solubilisation capacity for both drugs as demonstrated by flow-through studies and in vitro lipolysis studies. High loading of SNEDDS to Syloid 244 and 3050 silicas (2:1 w/w) allowed clinically translatable amounts of both NFX and BNZ to be loaded. Tablets prepared from NFX-BNZ combined SNEDDS loaded on Syloid 3050 silicas demonstration near complete dissolution in the flow through cell apparatus compared to NFX and BNZ commercial tablets respectively (Lampit ® and Rochagan ®). NFX-BNZ-SNEDDS demonstrated nanomolar efficacy in epimastigotes and amastigotes of T. cruzi with acceptable selectivity indexes and demonstrated enhanced survival and reduced parasitaemia in acute murine experimental models of CD. Thus, the results presented here illustrate the ability for an easily scalable and personalised combination oral therapy prepared from GRAS excipients, enabling treatment access worldwide for the treatment of CD.

AB - Chagas disease (CD) is a parasitic zoonosis endemic in Central and South America affecting nearly 10 million people, with 100 million people at high risk of contracting the disease. Treatment is only effective when received at the early stages of the disease and it involved two drugs (nifurtimox (NFX) and benznidazole (BNZ)). Both treatments require multiple daily administrations of high doses, suffer from variable efficacy and insufficient efficacy in chronic CD, many side effects, and a very long duration of treatment that results in poor compliance, while combined available therapies that lead to reduced duration of treatment are not available and polypharmacy reduces compliance and increases the cost further. Here we present self-nanoemulsified drug delivery systems (SNEDDS) able to produce easily scalable combined formulations of NFX and BNZ that can allow for tailoring of the dose and can be easily converted to oral solid dosage form by impregnation on mesoporous silica particles. SNEDDS demonstrated an enhanced solubilisation capacity for both drugs as demonstrated by flow-through studies and in vitro lipolysis studies. High loading of SNEDDS to Syloid 244 and 3050 silicas (2:1 w/w) allowed clinically translatable amounts of both NFX and BNZ to be loaded. Tablets prepared from NFX-BNZ combined SNEDDS loaded on Syloid 3050 silicas demonstration near complete dissolution in the flow through cell apparatus compared to NFX and BNZ commercial tablets respectively (Lampit ® and Rochagan ®). NFX-BNZ-SNEDDS demonstrated nanomolar efficacy in epimastigotes and amastigotes of T. cruzi with acceptable selectivity indexes and demonstrated enhanced survival and reduced parasitaemia in acute murine experimental models of CD. Thus, the results presented here illustrate the ability for an easily scalable and personalised combination oral therapy prepared from GRAS excipients, enabling treatment access worldwide for the treatment of CD.

KW - Chagas disease

KW - trypanosomiasis

KW - self-nanoemulsifying drug delivery systems (SNEDDS)

KW - Nifurtimox

KW - Benznidazole

KW - silicon dioxide (silica)

KW - solid self-nanoemulsifying drug delivery systems (Solid-SNEDDS)

U2 - 10.3390/pharmaceutics14091822

DO - 10.3390/pharmaceutics14091822

M3 - Article

SN - 1999-4923

VL - 14

JO - Pharmaceutics

JF - Pharmaceutics

IS - 9

M1 - 1822

ER -

Solid nanomedicines of nifurtimox and benznidazole for the oral treatment of Chagas disease

Abstract

Funding

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this