Praziquantel Nanoparticle Formulation for the Treatment of Schistosomiasis

Abstract

Schistosomiasis, a parasitic disease affecting around 250 million people globally, primarily children, necessitates the urgent development of pediatric praziquantel formulations, as outlined in the WHO neglected tropical diseases roadmap 2021–2030. We developed a low-cost PZQ nanoformulation utilizing a self-nanoemulsified delivery system (SNEDDS-PZQ). Physicochemical characterization confirms its hydrodynamic size and suitability for semi-industrial pilot batch production. Toxicity studies across multiple models demonstrate its safety profile. In vivo studies in schistosomiasis animal models reveal significant parasite load reduction (over 95%) with a single oral dose of 200 and 400 mg/kg of SNEDDS-PZQ, surpassing free praziquantel efficacy. Pharmacokinetic analyses demonstrate increased PZQ blood levels postadministration of SNEDDS-PZQ. Our findings highlight the promise of this innovative approach in pediatric schistosomiasis treatment by using this nanotechnology as a delivery system, offering potential for widespread application.

Introduction

Schistosomiasis, caused by parasitic flatworms of the genus Schistosoma, affects approximately 240 million individuals worldwide, with preschool children bearing the highest burden. Among the species of Schistosoma that infect humans, S. mansoni predominantly afflicts regions in Africa, the Near East, and South America. Notably, hepatosplenomegaly constitutes a hallmark symptom of this disease, underscoring its considerable morbidity.1 In children, schistosomiasis can cause anemia, malnutrition, and stunted growth, making it hard for them to attend school and do well. Consequently, preventive measures in endemic areas are imperative. For decades, control of schistosomiasis in individuals, communities, and nationwide mass drug administration programs has relied mainly on treatment with praziquantel (PZQ). However, PZQ faces challenges such as low solubility and oral bioavailability, which hinder its formulation for pediatric use and treatment effectiveness. Recognizing these obstacles, the WHO issued a roadmap in 2021 advocating for accelerated control and elimination of poverty-associated diseases by 2030, highlighting the necessity for pediatric PZQ formulations.

Treating preschool-aged children for schistosomiasis has remained particularly challenging due to the lack of a pediatric formulation. In response to this unmet need, the Pediatric Praziquantel Consortium has developed a novel pediatric treatment option based on an orally dispersible tablet containing levopraziquantel (L-PZQ), the biologically active PZQ enantiomer. Compared with the available PZQ tablets, the palatability of the new tablet has been improved because the existing PZQ formulation is a racemic mixture of levopraziquantel (L-PZQ) and Dextropraziquantel (D-PZQ). Only one of these components, L-PZQ, is pharmacologically active, while the inactive D-PZQ significantly contributes to the bitterness that complicates pediatric treatment. This development represents an important advancement; however, further innovations addressing cost-effectiveness and scalability remain critical for mass adoption in resource-limited settings. To address these remaining challenges, various innovative technologies, including lipid nanocarriers, have garnered attention for enhancing PZQ’s solubility and absorption.

Among these, the self-nanoemulsified delivery system (SNEDDS) presents a notable approach, characterized by an anhydrous formulation offering reduced administration volume-particularly crucial for pediatric use. Comprising oil and surfactant blends, SNEDDS spontaneously emulsifies upon contact with gastrointestinal fluids, offering advantages such as scalability and cost-effectiveness, making it an attractive option for addressing neglected diseases like schistosomiasis. This nanotechnology-based delivery system addresses limitations of conventional drugs such as praziquantel, significantly improving efficacy (as demonstrated in our results). This strategy holds
potential for enhancing the effectiveness of other drugs, offering a valuable tool to overcome pharmacokinetic challenges. Another significant challenge in administering praziquantel (PZQ) is its bitter taste, which poses a particular obstacle in pediatric populations. However, this issue may be alleviated by the SNEDDS formulation. The proposed SNEDDS system in this article allows for two viable administration routes to address this challenge: (1) an anhydrous oil-based mixture incorporating lipophilic flavor maskers for direct swallowing, and (2) a predispersed nanoemulsion in an aqueous continuous phase, enabling the incorporation of aqueous flavor maskers. For the second option, patients can consume the dispersion as a flavored aqueous solution, which can significantly mask the  bitterness.

Future product design will optimize the preferred administration method. It is important to note that we present a preclinical prototype that needs to be further developed with a focus on end-users. This article contributes by offering a feasible technological solution that should be refined for clinical applications. This study presents the development and preclinical evaluation of a novel and low-cost PZQ nanoformulation for schistosomiasis treatment. Through rigorous physicochemical characterization and comprehensive in vitro and in vivo assessments across various experimental models, we establish the formulation’s stability, scalability, safety, and efficacy.

Notably, in a murine model of schistosomiasis, we demonstrate the therapeutic effectiveness of SNEDDS-PZQ, surpassing free PZQ. Additionally, pharmacokinetic analyses reveal elevated PZQ blood levels following administration of SNEDDS-PZQ. Finally, we showcase the scalability of SNEDDS-PZQ for industrial production through successful batch production in a semi-industrial pilot batch setting. The industrial scalability of this prototype is a significant advantage, especially considering the cost constraints associated with treating neglected diseases. Our design prioritizes affordability within this context. An illustrative overview of the experimental strategies is provided in Figure 1.

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Excipients mentioned in the paper: Kolliphor HS 15 and SPAN 80

Ana C. Mengarda, Bruno Iles, Vinícius C. Rodrigues, Ana Luiza Lima, Victoria P. Machado, Walberson S. Reatgui, Patricia Bento da Silva, Marina A. Radichi, Taís C. Silva, Fernanda S. Teixeira, Maria C. Salvadori, Marina M. Simões, Karen L. R. Paiva, Cesar K. Grisolia, Maria L. Fascineli, Sebastião W. Silva, Marcílio S. S. Cunha-Filho, Sônia N. Bao, João P. F. Longo, and Josué de Moraes, ACS Applied Nano Materials Article ASAP, DOI: 10.1021/acsanm.4c06757

Read also our introduction article on Parenteral Excipients here: