Hot melt extruded High-Dose amorphous solid dispersions containing lumefantrine and Soluplus

Abstract

Over the last 15 years, a small number of paediatric artemisinin-based combination therapy products have been marketed. These included Riamet® and Coartem® dispersible tablets, a combination of artemether and lumefantrine, co-developed by the Medicines for Malaria Venture and Novartis. Disappointingly, patient compliance, requirement for high-fat meal, and sporadic drug dissolution behaviours following administration still result in considerable challenges for these products. The first and foremost barrier that needs addressed for successful delivery of the artemether/lumefantrine combination is the poor solubility of lumefantrine within the gastrointestinal fluids. In this work, amorphous solid dispersions of lumefantrine within Soluplus®-based matrices have been manufactured using hot melt extrusion as a potential formulation strategy to achieve enhanced dissolution and apparent solubility. The drug loading capacity of Soluplus® to accommodate amorphous lumefantrine, whilst ensuring improved in-vitro dissolution performance, was investigated. The extrusion process employed a variety of processing parameters, including various temperature profiles and different production scales. The influence of variation in extrusion conditions upon the physical stability of manufactured amorphous solid dispersions was also examined. This allowed for a greater understanding of the role of extrusion processing conditions on the performance of supersaturated amorphous solid dispersions during dissolution and storage. This may allow for the design and manufacture of drug enabled formulations with lower drug dosing and thus a lower risk of adverse effects.

Introduction

Malaria continues to be a life-threatening infectious disease with deaths occurring as fast as 24 h after initial onset of symptoms. In 2021, the global tally of malaria cases was reported to be 247 million, which resulted in 619,000 deaths (World Health Organization, 2022). Moreover, the same report also acknowledged that “children aged under 5 years, pregnant women, and people with HIV or AIDS are at higher risk of severe infection”. Tragically, young children are the most vulnerable, accounting for almost 80 % of all malaria-associated deaths. In 2015, the World Health Organization issued a global technical strategy to address growing concerns around malaria treatment. Sadly, targets set to reduce case incidence and death rates globally, particularly in children, remain unmet.

Until 2009, there was no artemisinin-based combination therapy (ACT) specifically developed for paediatric use. In general, paediatric treatment involved administration of crushed tablets, with dose adjustment. Over the past decade, with increasing recognition of the vulnerability of young children to malaria, as well as the emergence of new drug compounds and combinations that offer improved safety and efficacy, child-friendly antimalarial fixed-dose combination (FDC) products have been marketed. Several formulations have been developed for this purpose including once-daily Eurartesim® (a piperaquine tetraphosphate and artenimol combination) and Pyramax® Granules (sachet containing granules of artesunate and pyronaridine combination) (Medicines for Malaria Venture, 2015). However, undoubtedly, Coartem® which is a taste-masked orodispersible tablet formulation co-developed by the Medicines for Malaria Venture and Novartis (2009) has gained the most attention for its potential to improve dosing accuracy and patient compliance,

Coartem® is a combination product that provides effective antimalarial treatment through the rapid action of artemether (ART) coupled to long-acting lumefantrine (LUM). Despite Coartem® offering improved patient compliance, it is well known that lumefantrine suffers from poor oral bioavailability, owing to the poor solubility and permeability (Wahajuddin et al., 2011). This leads to a requirement to increase dosing or risk treatment failure (Ogutu et al., 2023). In addition, lumefantrine is highly lipophilic and has been shown to exhibit significant food effects, with a 16-fold bioavailability increase when administered with a high-fat meal (Djimdé and Lefèvre, 2009); (Jain et al., 2017). It is therefore recommended that lumefantrine be administered with a high-fat meal, which can be particularly challenging in poverty-stricken areas, where malaria remains intractable. Moreover, the typical symptoms of malaria, which include vomiting and diarrhoea, are also obstacles to optimal efficacy. Where Coartem® Disperse is used (in paediatric patient), the requirement for water to facilitate dispersion of tablets may also introduce additional risk factors such as potential contamination, particularly where clean water is in short supply.

Recent approaches, reported in the literature, to enhance the therapeutic efficacy of Coartem® include the use of nanoparticles (Armstrong et al., 2023), cyclodextrin nano-sponges (Pawar and Shende, 2020), mesoporous silica (Bhattacharyya and Ramachandran, 2022), microneedle arrays (Volpe-Zanutto et al., 2021), nanocrystals (Hassan Shah et al., 2021) and amorphous solid dispersions (ASDs) (Bhujbal et al., 2021, Trasi et al., 2020). Amongst these, ASDs offer a significant opportunity to enhance the dissolution behaviour of poorly water-soluble drugs, bringing substantial opportunity to overcome the sub-optimal clinical performance of compounds that exhibit dissolution-limiting absorption. Over the course of the last ten years, there have been many techniques employed to manufacture amorphous drug platforms, including spray drying, solvent-evaporation, anti-solvent precipitation and hot melt extrusion (HME) (AL-Japairai et al., 2023, Trasi et al., 2020). In the context of formulating and manufacturing a drug product for extended use across sub-Saharan Africa, affordability and availability are two of the most critical factors that impede widespread access to medication (Armstrong et al., 2023, Yenet et al., 2023). In that case, HME presents particular benefits owing to it being continuous in nature, solvent-free, and easily “scalable”. Moreover, as a continuous process, HME offers the pharmaceutical industry a means of addressing process inefficiencies, improving manufacturing agility and thus, is a processing tool that can be used to enhance product quality whilst reducing production costs (Badman et al., 2019).

ASDs are well-known to be susceptible to physical stability issues during storage (Weuts et al., 2003). The high energy state of amorphous materials is prone to relaxation, leading to recrystallisation and ultimately loss of therapeutic benefit (Zhou et al., 2002). Moreover, physical instability of amorphous drug is often a major challenge in sub-Saharan conditions. Numerous attempts have been reported in the literature to probe not only successful formation of ASDs, but also appropriate stabilisation of these high energy systems. Well-reported stabilising strategies include the use of drug-polymer interactions, mathematical modelling to help select systems having superior drug-polymer miscibility and/or solubility (Tian et al., 2013, Li et al., 2016), physical entrapment either using high glass transition temperature (Tg) polymers or via porous silica-based materials.

This work describes the potential of HME as a continuous and agile drug product manufacturing technology to address the solubility challenges of lumefantrine.

This article investigates the impact of drug loading and HME processing conditions on ASD formation and the resistance of manufactured ASDs to recrystallisation under accelerated conditions. To achieve these aims, this study was set out to: (1) produce ASDs consisting of LUM within Soluplus®-based matrices at two drug loadings (30 % w/w and 50 % w/w respectively); (2) investigate the role of HME processing parameters, including barrel temperature profile and extruder scale, upon drug amorphization in ASDs; (3) understand how oversaturated amorphous drug formulations, manufactured by intense processing, impact drug product performance (stability and drug release characteristics).

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Materials

Lumefantrine (LUM) was sourced from Kemprotec Limited, UK. Soluplus® (SOL), Kolliphor® SLS Fine (SLS) and Kolliphor® PS80 (T80), were provided by BASF Corporation, USA. High-purity solvents and reagents, including acetonitrile (ACN), methanol (METH), acetone, sodium phosphate tribasic dodecahydrate (TSP) and hydrochloric acid (HCl), essential for HPLC mobile phase and dissolution medium preparation, were procured from Fluka Honeywell, UK.

Shu Li, Zi’an Zhang, Wenjie Gu, Maël Gallas, David Jones, Pascal Boulet, Lindsay M. Johnson, Victoire de Margerie, Gavin P Andrews, Hot melt extruded High-Dose amorphous solid dispersions containing lumefantrine and Soluplus,
International Journal of Pharmaceutics, 2024, 124676, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124676.

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