Fabrication and characterization of taste-masked core-shell nanofibre mats for dual drug delivery of antihypertensives in pediatrics

Abstract

Drug adherence in pediatrics can be challenging due to bitter drug taste, dysphagia and polypharmacy. With pediatric hypertension on the rise worldwide, this study investigated the use of electrospinning to create a novel taste-masked, fixed-dose combination of lisinopril dihydrate (LIS) and amlodipine besylate (AML) for paediatric use. Electrospun nanofibres of the antihypertensives were formulated as core–shell fibres with polyvinylpyrrolidone (PVP), and Eudragit® EPO (EEPO) by applying an electrical charge to a viscous mixture of the drugs, polymers and solvents. The drug loading, release kinetics, morphology, thermal analysis, physical and solid-state characterization of the fibre mats were evaluated. Taste-masking was investigated in vitro by electronic-tongue analysis. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses showed smooth, non-beaded core–shell fibres with diameters in the nanorange. Fourier transform infra-red (FTIR) spectroscopy and x-ray diffraction (XRD) studies confirmed the drugs were amorphously dispersed within the fibres and thermal analysis studies showed acceptable stability profile of the formulations. Both drugs were over 90 % released in 15 mins consistent with immediate release formulations. The e-tongue mean sensor response plot showed the nanofibre mats achieved a statistically significant enhanced taste-masking (p < 0.0001) compared to raw amlodipine which registered a high bitterness reading of 87 mV. This study therefore indicates that coaxial electrospinning may be used to produce a fixed-dose taste masked nanofibre mat of LIS and AML that can potentially be used to improve adherence in children.

Introduction

Non-adherence or poor adherence to therapy occurs when a patient does not take medication according to the prescribed dosage regimen (Vrijens et al., 2012); this may result in poor treatment outcomes, drug resistance, complications and financial losses (Muture et al., 2011). Poor adherence is prevalent in both adults and children, although it is more common in pediatrics (Kardas et al., 2021) According to Mcgrady and Hommel, out of approximately 63 % of children and adolescents diagnosed with chronic illnesses, 50 % to 88 % of them are non-adherent to their prescribed medications (McGrady and Hommel, 2013) and this can be attributed to poor tasting drugs, dysphagia and polypharmacy (Bukhary et al., 2018; Uestuener et al., 2014; Chachlioutaki et al., 2020).

Children are more sensitive to bitter, sour or aversive tastes, a major deterrent to compliance to therapy (Felton, 2018), therefore, age-appropriate dosage forms are required to encourage adherence in pediatrics (Stojmenovski et al., 2024). Some diseases associated with adults do not have age-appropriate dosage forms available for treatment in children. In such uncommon conditions, children may be prescribed unlicensed medicines or given adult medications for off-label use (Chappell, 2015). These medications are either crushed, broken, mixed with food or reconstituted with sweeteners; these practices are associated with difficulty in breaking, uneven doses, stability issues and loss of drug mass (Poller et al., 2017).

The European Union Paediatric Regulation of 2006 requires that appropriate dosage forms for children be developed without subjecting them to unnecessary clinical trials (European Medicines Agency, 2007; Steiner et al., 2024). Also, the use of animals and humans in research is discouraged where a suitable in vitro technique is available especially at the early stage of drug development. Consequently, several studies have employed the electronic tongue as a suitable alternative to in vivo studies in investigating the palatability of food and drugs (Abdelhakim et al., 2021; Georgieva et al., 2020; Immohr et al., 2017; Keating et al., 2020; Steiner et al., 2024; Tawfik et al., 2021). The e-tongue assesses the bitterness or aversiveness of a drug when it is subjected to its sensor arrays and resulting data can be interpreted by noting the difference in sensor membrane potential between the values obtained from the reference solution and that from the sample solution.

High blood pressure (HBP) is a major risk factor in cardiovascular and renal diseases, early detection and treatment is necessary to prevent morbidity and mortality (Burrello et al., 2018). It is a chronic health condition that requires daily drug administration with best treatment options involving the use of multiple drugs with different mechanisms of action. Adherence is improved if the medications occur as a fixed-dose combination (FDC). Cardiovascular incidences occur mostly in geriatrics but unfortunately, we now see an increase in HBP in pediatrics (Thomas et al., 2022). Song et al. reported a global increase in paediatric hypertension of 75 % to 79 % from 2000 to 2015 and in 2015 alone, they reported an increase of 4.32 % among 6-year-olds, 3.28 % in 19-year-olds and 7.86 % in children aged 14 years (Song et al., 2019). This trend has been attributed to the increased prevalence of obesity in children (Ashraf et al., 2020; Thomas et al., 2022) and treatment with more than one antihypertensive has been shown to improve blood pressure control (Flynn et al., 2017). In these populations, swallowing difficulties, bitterness of drugs and polypharmacy discourage adherence to therapy (Abdelhakim et al., 2020; Bukhary et al., 2018; Punnapurath et al., 2021; World Health Organization, 2023). There are currently no child-friendly formulations available for the management of this disease in children (Ferrarini et al., 2013, Uestuener et al., 2014) and poor management of childhood hypertension has been observed to be associated with later essential hypertension in adults and persistent cardiovascular events (Song et al., 2019).

Amlodipine besylate (AML) and lisinopril dihydrate (LIS) are two antihypertensives commonly used in the management of paediatric hypertension (Thomas et al., 2022). AML is a calcium channel blocker; its bitter taste poses a challenge in its use in pediatrics (Uestuener et al., 2014). LIS is an angiotensin-converting enzyme inhibitor; it is more palatable (Ferrarini et al., 2013), and has a longer duration of action compared to AML. Though there are no known amlodipine/lisinopril fixed-dose antihypertensive in the market, these can be prescribed together to exert a synergistic blood pressure lowering effect.

Recently, drug delivery using nanofibres has been explored as a unique, innovative and versatile way of administering medicines into the body (Ilomuanya et al., 2023). Nanofibres have a high surface area to volume ratio, high porosity and good mechanical strength (Can Suner et al., 2022; Jiffrin et al., 2022, Gareth et al., 2018) and therefore are suitable carriers for drugs. A wide variety of synthetic and natural polymers can be used to control the release kinetics of incorporated drugs, ensure targeted release of the drug, enhance the drug loading properties of the nanofibres, and improve the palatability of drugs (Dziemidowicz et al., 2021; Grimaudo et al., 2020, Samia et al., 2023; Wildy and Lu, 2023).

Polyvinylpyrrolidone (PVP) is a hydrophilic, generally recognized as safe (GRAS) polymer with very good electrospinning properties (Illangakoon et al., 2014). It has been used together with cyclodextrin to taste-mask bitter drugs (Samprasit et al., 2018) and has also found application in facilitating electrospinning when used in combination with polymers that have poor intrinsic electrospinning properties. Eudragit® EPO (EEPO) is a pH dependent taste-masking polymer; drug release from this carrier polymer is expected to occur at a pH < 5.0. This implies that the incorporated drugs release will be prevented in the salivary fluid pH of 7.4 but will be delayed until the delivery system reaches the acidic environment of the stomach. Here we propose that the combination of PVP and EEPO will have a synergistic effect, resulting in both taste masking of incorporated drugs and suitable electrospinnability.

A limited amount of work on fixed-dose combination involving AML and other hypertensives has been performed. Trenfield et al. investigated the non-destructive methods of assessing the quality of LIS and AML in 3D printlets using NMR spectroscopy (Punnapurath et al., 2021); while this study is mainly focused on quality control it also supports the desirability of a fixed-dose combination of these drugs (Trenfield et al., 2020). Bukhary et al. reported the successful characterization of a fixed-dose combination of AML and valsartan as fast dissolving formulation using monoaxial electrospinning (Bukhary et al., 2018). The authors acknowledged the potential of using the electrospun fibres containing multiple drugs to aid adherence in geriatrics.

Electrospinning has been previously utilized in the taste-masking of bitter drugs (Tawfik et al., 2021, Wu et al., 2015). Abdelhakim et al. reported the effectiveness of Kollicoat® smartseal and Eudragit® EPO polymers in taste-masking chlorpheniramine maleate using coaxial electrospinning (Abdelhakim et al., 2021) while Samprasit et al. investigated the use of PVP and cyclodextrin together to taste mask meloxicam, a bitter tasting, non-steroidal anti-inflammatory drug (Samprasit et al., 2015). In both studies, electrospinning was used to formulate nanofibres containing a single drug.

In this study we investigate the effectiveness of PVP and EEPO polymers in fabricating smooth, non-porous, beadless co-axial fibres to deliver a taste-masked, fixed-dose combination of LIS and AML for treatment of paediatric hypertension. As a stretch objective, it is proposed that nanofibre mats fabricated with taste-masking polymers and the dual drug loading will improve drug adherence in children by targeting adherence issues such as drug bitterness, polypharmacy and swallowability.

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Materials

Eudragit® EPO (EEPO), also known as basic butylated methacrylate copolymer, was donated by Evonik (Darmstadt, Germany), polyvinyl pyrrolidone (PVP, 360,000 MWT) was purchased from Alfa Aesar, MA, USA, lisinopril dihydrate (LIS) from Acros Organics, amlodipine besylate (AML) was purchased from LKT laboratories, MN, USA, 99 % (v/v) methanol, 99 % (v/v) ethanol, and hydrochloric acid were from Fisher Chemicals (Loughborough, UK). Phosphate buffered saline (PBS) tablets pH 7.4 was purchased from MP Biomedicals (Santa Ana, California, USA) and formvar/carbon 300 mesh (pack of 25) from Agarscientific, UK. Tartaric acid was purchased from Sigma Aldrich (Dorset, UK) and potassium chloride was obtained from Scientific Laboratory Supplies (Nottingham, UK). All solvents used were of analytical grade or HPLC grade.

Uloma N. Ubani-Ukoma, Xiunan Li, Mahmood Faiyaz, Maryam Parhizkar, Duncan Q.M. Craig, Hend E. Abdelhakim, Fabrication and characterization of taste-masked core-shell nanofibre mats for dual drug delivery of antihypertensives in pediatrics, International Journal of Pharmaceutics, Volume 690, 2026, 126541, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.126541.

Read also our introduction article on Taste Masking here: