HME coupled with FDM 3D printing of a customized oral solid form to treat pediatric epilepsy

Abstract

Interest in hot-melt extrusion (HME) and fused deposition material (FDM) printing has increased in recent years, for the production of tailored medications for patients with specific requirements, such as pediatrics. Liquid forms are often preferred for children but these forms are less stable than oral solid forms (such as tablets or powder), requiring preservative not always suitable for children. Then, the aim of this study is to develop a dose-adapted dispersible 3D printed forms using HME with FDM to treat pediatric epilepsy. Polyethylene oxide (PEO)-based 3D printed forms were developed with sodium valproate (VAL) as model drug at different concentrations. The effects of polyethylene glycol (PEG)’s molecular weight (PEG6K and PEG35K) used as plasticizer on the formulations’ mechanical, thermal and rheological properties were investigated. Formulation with 10 % (w/w) of VAL were printed with PEG6K and PEG35K, while only PEG35K was suitable for extruding and printing a formulation containing 30 % (w/w) of VAL due to its rheological properties. Steric exclusion chromatography coupled with refraction index was used to quantify VAL content, indicating uniform concentration in the filament after extrusion. Dissolution test in acidic media display over 80 % of VAL released within 20 to 25 min, reaching the Eur. Ph. Criteria of a rapid release. The outcomes of this study present suitable formulations to produce personalized dispersible form using HME with FDM 3D printing to treat pediatric epilepsy (1 month to 4 years old patients with dosage from 18 to 247 mg/kg/day) for the treatment of epilepsy.

Introduction

Among the different routes of drug administration, oral administration is often preferred due to its convenience and cost-effectiveness. Tablets represent more than 50 % of all marketed solid oral pharmaceutical preparations as they are easier and more economical to develop, manufacture, transport and store than liquid forms (Kotsybar et al., 2023). However, they are less suitable for patients with swallowability issues, such as pediatric and geriatric populations and come with specific dosage, hard to adapt to patient’s weight, which is mandatory for children. Epilepsy, is the most frequent chronic neurologic disease affecting pediatric patients (Aaberg et al., 2017) widely treat with sodium valproate (VAL), a first-generation antiepileptic. Due to its poor solubility and high permeability sodium valproate (VAL) is a Class II drug in the biopharmaceutical classification system (Chang, 1979). Epilepsy treatment requires high flexibility with a daily dose of 10 to 30 mg/kg per day divided in 1 to 3 intakes (“Easyprep Pédiatrie”; Depakine 200 mg/ml, 2024). Due to the quick increase of patients’ weight in the first months of life, the treatment must be flexible to provide a dose adapted. As the dose is usually divided in 2 doses per day, a 1-month old child (3,6 kg) medicated with 10 mg/kg requires 18 mg per intake, while a 4-years old (16.2 kg) child medicated with 30 mg/kg requires 243 mg per take (WHO, 2022). With these specifications, solids forms are limited while liquid formulations offer more dose flexibility.

However, liquid forms require the use of conservatives for stability issues and involve higher transport and packaging costs (Mfoafo et al., 2021).3D printing (3DP) is a technology that can meet all the requirements of solid and liquid forms with great dosing flexibility, the development of dispersible forms to ease the administration and storage. Among the various 3D printing techniques, fused deposition modeling (FDM) stands out due to its cost-effectiveness, absence of post-processing steps, and solvent-free composition (Cailleaux et al., 2021). FDM 3D printed filaments are prepared using hot melt extrusion (HME), widely used in the pharmaceutical field to produce solid dispersions. Nonetheless, HME coupled with FDM raises challenges with risks of drug’s thermal degradation. To prevent this, polymer with low melting point and plasticizer properties such as Polyethylene glycols (PEG) can be used (Hoffmann et al., 2022, Xu et al., 2020). PEG, marketed over a wide range of molecular weights, are often used in pharmaceuticals formulations as viscosity modifiers. They are classified as PEGs when molecular weight is below 100 K g/mol, while those with higher molecular weights are classified as polyethylene oxides (PEOs) (Ma et al., 2014).

The aim of this study is to formulate an FDM-printed oral solid form and, considering the targeted population, the printed forms must be dispersible in water before administration. PEO 100 K g/mol was selected as polymer carrier due to its low processing temperature (60 – 100 °C), water solubility and good processability in HME and FDM (Baird et al., 2010, Melocchi et al., 2016). PEGs were used as plasticizers to improve processability of the formulation. While several studies have investigated the effect of the polymeric carrier molecular weight on FDM printed forms, few studies focused on the influence of the plasticizer’s length, hence, formulations with PEG 6 K g/mol (PEG6K) and PEG 35 K g/mol (PEG35K) were prepared (Cantin et al., 2016, Isreb et al., 2019). The formulations were characterized by XRPD, TGA and DSC to investigate the effect of HME and FDM printing on the physico-chemical properties of VAL, PEO and PEGs. As the flowing property is a key parameter in HME and FDM printing, a rheological study was performed to determine the influence of PEGs’ molecular weight and VAL loading on the formulation’s viscosity. Then, filament’s flexural modulus was determined using three-point bend test to assess their flexibility. Considering the need of dose flexibility, the drug load of the formulation, as well as the height and infill density of the printed forms were varied. Due to the pediatric targeted population, the resulting printed forms must be dispersed in water before administration in solution. Hence, disintegration tests were performed in water. Then, the dissolution profiles of VAL were determined in gastric media to mimic oral administration. Finally, a 3-months stability study was performed on filaments and printed forms stored at room temperature and a relative humidity of 40 %.

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Materials

Polyethylene glycol 35 K g/mol (PEG35K), 6 K g/mol (PEG6K) and polyethylene oxide 100 K g/mol (PEO), sodium valproate (VAL) salt 99 % purity, sodium chloride, 0.1 mol/l hydrochloride acid (HCl) and acetonitrile HPLC-grade were purchased from Sigma-Aldrich. For analysis, ultrapure water was produced by a Synergy ® UV water system (Millipore SA, Molsheim, France). All solvents were of analytical grade, unless otherwise specified.

M. Monteil, N.M. Sanchez-Ballester, A. Aubert, O. Gimello, S. Begu, I. Soulairol, HME coupled with FDM 3D printing of a customized oral solid form to treat pediatric epilepsy, International Journal of Pharmaceutics, Volume 673, 2025, 125345, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.125345.

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