How sugar types and fabrication methods affect palatability in paediatric-friendly oromucosal pullulan films of chlorpromazine hydrochloride

Introduction

Developing age-appropriate medicines for children lies in the delicate balance between effectiveness, safety and patient acceptability (Malkawi, Alrafayah, Alhazabreh, Abulaila, & Al-Ghananeem, 2022). Swallowability, ease of administration and the organoleptic properties of a dosage form are determinant factors in the overall acceptability of a medication (Ranmal et al., 2018). Especially among paediatric patients, palatability is crucial to promote adherence, as children may refuse to take medication that has bad taste or texture, as in the case of some antibiotics (Baguley, Lim, Bevan, Pallet, & Faust, 2012), which in turn could lead to poor treatment outcomes (El-Rachidi, LaRochelle, & Morgan, 2017).

Orally disintegrating films (ODFs) offer a highly attractive solid dosage form option for paediatric patients, aligning with the recommendations of the World Health Organization (WHO) (Committee, Preparations, Prequalification, & Programme, 2007) due to their rapid dissolution in the mouth, eliminating the need for water (Nagaraju et al., 2013; Laffleur & Keckeis, 2020; Preis, 2015; Bala, Khanna, Pawar, & Arora, 2013; Deng, Shen, Yang, & Shen, 2021). ODFs have been found to be acceptable not only by infants and preschool children (Orlu, Ranmal, Sheng, Tuleu, & Seddon, 2017) but also by neonates (Klingmann et al., 2020), with Setofilm® being the first prescription product indicated for preventing chemotherapy and radiotherapy-induced nausea and vomiting in children as young as six months (Ferlak, Guzenda, & Osmałek, 2023). Solvent casting has traditionally been the preferred method for fabricating ODFs, (Rédai et al., 2021; Shahzad et al., 2020; Musazzi, Dolci, Albertini, Passerini, & Cilurzo, 2019; Khanh et al., 2023) though it often involves the use of organic solvents and plasticizers that may pose risks to children. Emerging alternatives like electrospinning (Ravasi et al., 2023; Chachlioutaki et al., 2020; Olechno, Grilc, Zupančič, & Winnicka, 2022; Patil, Celebioglu, & Uyar, 2023) and 3D printing (Vakili, Nyman, Genina, Preis, & Sandler, 2016; Racaniello et al., 2023; Thabet, Lunter, & Breitkreutz, 2018; Sjöholm & Sandler, 2019; Oh, Jin, Park, Park, & Lee, 2020) offer safer, ambient-temperature fabrication, ideal for thermolabile compounds. Electrospinning produces nanofibers with high surface area and fast drug release properties, making it suitable for paediatric formulations (Tan et al., 2022). Meanwhile, 3D printing enables personalized medications with precise dosing tailored to individual patient needs (Muhindo, Elkanayati, Srinivasan, Repka, & Ashour, 2023). Pullulan, a GRAS (Prajapati, Jani, & Khanda, 2013) natural polysaccharide, serves as a primary component in electrospun oral films for many active pharmaceutical ingredients (API): sildenafil (Ravasi et al., 2023), aspirin (Qin, Jia, Liu, Kong, & Wang, 2019), vitamin C (Cheng et al., 2024), ampicillin (Ponrasu, Chen, Chou, Wu, & Cheng, 2021), prednisolone (Celebioglu, Wang, Kilic, Durgun, & Uyar, 2021), carvedilol (Domokos et al., 2019), tetracycline (Hsiung et al., 2022), griseofulvin (Hsiung, Celebioglu, Kilic, Durgun, & Uyar, 2023) and even probiotic bacteria such as Lactobacillus rhamnosus GG (Akkurt, Renye, & Tomasula, 2022). Additionally, pullulan shows promise as a feedstock material for 3D printing processes for the construction of scaffolds (Rimann et al., 2022), microneedles (Fonseca et al., 2020) as well as for tailored oral films (Yu, Kim, & Park, 2022; Elbadawi, Nikjoo, Gustafsson, Gaisford, & Basit, 2021).

A major challenge associated with orodispersible film technology is masking the bitter taste of certain drugs (Mfoafo, Omidian, Bertol, Omidi, & Omidian, 2021), which can result in children refusing to take their medication. To improve palatability and adherence, various strategies have been developed such as chewable chocolate-based tablets of midazolam (Cheung et al., 2018; Salman et al., 2018), taste-masked coated-granules of sodium phenylbutyrate (Guffon, Kibleur, Copalu, Tissen, & Breitkreutz, 2012) and a baclofen-loaded oral jelly (Shetty & Thakkar, 2023). Taste masking techniques include adding flavors, sweeteners (Lee & Owyang, 2019) and bitter receptor blockers (Andrews et al., 2021), using lipophilic vehicles (Zhang et al., 2020), amino acids (Pydi et al., 2014), cocrystals (Soliman, Kandil, & Abdou, 2020) and ion-exchange resins (Bhise, Shaikh, & Bora, 2008), spray congealing with lipids (Qin et al., 2019), the formation of inclusion complexes with cyclodextrins (Del Valle, 2004), film coating (Joshi & Petereit, 2013), salts (Aitipamula, Wong, Chow, & Tan, 2014), or polymeric membranes (Sohi, Sultana, & Khar, 2004). Sugars are among the most common excipients used for developing palatable formulations, with natural sweeteners, like sucrose, glucose, fructose being prevalent in syrups (Al Humaid, 2018), while non-nutritive sweeteners are alternatives to address obesity and dental issues. High-intense sweeteners like sucralose (Du Bois & Prakash, 2012) are increasingly used in food, beverages and pharmaceuticals due to their high potency (Yu et al., 2011; Yu et al., 2010; Youssef, Korany, Khamis, Mahgoub, & Kamal, 2011; Wang et al., 2021).

Sugar intake from drug formulations is typically minimal and short-term compared to dietary sources (Sundar, 2012). While sugars in medications may contribute to overall intake, their role in enhancing medication compliance and patient acceptance may outweigh potential dental risks (Sundar, 2012), especially with proper oral hygiene. Sweeteners like sucralose (Abdelkader et al., 2023), aspartame (Jadach, Misek, & Ferlak, 2023), xylitol (Matawo, Adeleke, & Wesley-Smith, 2020) and others (Cupone et al., 2023) have been used in ODFs to mask the bitter taste of the drugs. However, there has been no prior report on the effect of different sugars on their taste masking efficacy in ODFs.

In this work, the effect of sugar type and fabrication method were tested on the sensory characteristics of paediatric-friendly oromucosal films containing the bitter-tasting drug chlorpromazine hydrochloride (CHZ) (Haraguchi et al., 2019; Kojima et al., 2021), commonly used for its antiemetic and antipsychotic properties (Dundee, 1954). Traditional oral forms of CHZ such as oral tablets (10–200 mg) and oral solution (25 mg/5 mL), can be challenging for children due to taste and swallowing difficulties. As oromucosal film offers a convenient and non-invasive way for drug administration to children, that can improve patient compliance and treatment outcomes (Khan, Kirby, Bryson, Shah, & Rahman Mohammed, 2022), the aim of this study was to prepare CHZ more palatable and easy to administer in paediatric patients by using sugar-based oromucosal electrospun and 3D printed films. Specifically, ten sweeteners were chosen: the high-caloric sucrose, fructose, glucose, and maltose; five sugar alcohols—sorbitol, mannitol, xylitol, erythritol and isomalt; and one high-intensity sweetener, sucralose (sucralose >fructose, sucrose, xylitol>glucose, erythritol, sorbitol, mannitol> maltose, isomalt, in decreasing order of sweetness potency) (Table S1). A human taste panel, recognized as the gold standard for evaluating the overall pharmaceutical formulation palatability, was used to assess the palatability of the oromucosal films, whereas the electronic tongue (e-tongue) (Abdelhakim, Coupe, Tuleu, Edirisinghe, & Craig, 2019; Hu, Fitaihi, Abukhamees, & Abdelhakim, 2023) was used to assess the taste of the films in addition to the human taste panel (Abdelhakim, Williams, Craig, Orlu, & Tuleu, 2020; Ranmal et al., 2023) to evaluate the bitterness masking effect of the sugars.

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Materials

Pullulan (Pharmaceutical Grade, M_w ≈ 200 kDa) was kindly provided by Nagase group (Düsseldorf, Germany). Glucose, sorbitol, xylitol, sucralose, sucrose, fructose, isomalt, erythritol, mannitol and maltose were purchased from Fagron hellas (Fagron, Trikala, Greece). Chlorpromazine hydrochloride was obtained from Alpha Aesar (South Quay, Heysham, United Kingdom). Denatonium benzoate was purchased from Sigma-Aldrich (Dorset, UK). Reagents used in e-tongue testing included tartaric acid, potassium

Konstantina Chachlioutaki, Xiunan Li, Savvas Koltsakidis, Hend E. Abdelhakim, Nikolaos Bouropoulos, Dimitrios Tzetzis, Christina Karavasili, Dimitrios G. Fatouros, How sugar types and fabrication methods affect palatability in paediatric-friendly oromucosal pullulan films of chlorpromazine hydrochloride, Carbohydrate Polymers, Volume 348, Part A, 2025, 122802, ISSN 0144-8617, https://doi.org/10.1016/j.carbpol.2024.122802.

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