Exploring new buccal films based on hydroxyethyl cellulose and Linecaps® combination for the pediatric delivery of hydrophobic molecules

Abstract

Polysaccharides and starch derivatives can play a role in the development of buccal film and patches. Buccal films are a valid approach to the transmucosal administration of drugs. These drug-delivery systems are adaptable to the mucosal surface, while being particularly suitable for the pediatric population. This study explores the combination of polysaccharide-based films for the buccal administration of the poorly soluble drug, ibuprofen.

The films were obtained via the freeze-thaw technique using an innovative combination of two film-forming polymers of natural origin, i.e. hydroxyethylcellulose and a pea starch derivate (Linecaps®). Ibuprofen was selected as model drug to be loaded into the buccal formulation as a β-cyclodextrin complex. The produced films showed good physico-chemical and functional properties including homogeneous drug content, thickness, mechanical strength, mucoadhesion, thus guaranteeing suitable drug loading and applicability. In vitro, permeation studies of Ibuprofen buccal films were carried out using a synthetic biomimetic membrane, and rabbit mucosae tissue exhibited values of permeability fluxes in the same order of magnitude for the two tested membranes (1.51 × 10⁻² ± 0.33 × 10⁻² μg/cm²*s vs 1.21 × 10⁻² ± 0.18 × 10⁻² μg/cm²*s).

The release of the drug from the buccal film, the taste-masking and permeation properties suggested that the proposed combination of polysaccharides represent a potential formulation of mucoadhesive buccal films.

Introduction

Natural-derived polysaccharides have attracted research attention for the development of buccal formulations due to their biocompatibility, film-forming capability and mucoadhesive properties (Guru et al., 2023; Yu et al., 2018). Buccal drug administration is an attractive route for the systemic delivery of drugs and one that presents a series of advantages over traditional oral administration (Nair et al., 2023; Shipp et al., 2022). Specifically, the use of this administration route in the pediatric population is continuously increasing due to the ease of administration and the substantial enhancement in patient compliance (Abruzzo et al., 2017; Montero-Padilla et al., 2017; Rathbone et al., 2015). Indeed, the buccal route avoids hepatic first-pass metabolism (Adhikari et al., 2010), and gastrointestinal (GI) enzymatic degradation, allows administration to a highly vascularized area without enzymatic activity, and displays rapid action onset and quick elimination after detaching the dosage form (Lam et al., 2014; Patel et al., 2011). Several formulations, such as capsules, lozenges, tablets, sprays, mouthwashes, gels and, recently, films have been designed for buccal drug delivery over the past decades (Lee et al., 2000; Montenegro-Nicolini and Morales, 2017).

In this context, orally dissolving films (ODFs) have attracted particular attention as potential delivery systems for drug administration in the pediatric population (Ouda et al., 2020). Notably, the solid dosage forms specifically developed for administration to this population should comply with a series of requirements including acceptability, palatability, minimal dosing frequency, dose titration, possibility of weight-based dosing and easy administration. Furthermore, the excipients used should also be safe for the pediatric population (EMA, 2013; Ernest et al., 2010; Strickley et al., 2008; Weltgesundheitsorganisation, 2005). Mucoadhesive buccal films are flexible, easily adaptable to the surface of mucosa, thin, soft and developed to offer both local and systemic drug effects, resulting in an extended duration of activity (Aframian et al., 2006; Shady et al., 2022). Moreover, these dosage forms can disintegrate and dissolve quickly without the need of water and can withstand the damage caused by mouth movements (Borges et al., 2015; Dixit and Puthli, 2009; Krampe et al., 2016), making them suitable for the use in children.

Additionally, buccal administration can overcome the difficulties associated with swallowing conditions, such as dysphagia, that are observed with the use of tablets and capsules, as well as the unpleasant taste and inaccurate dosing observed with solution-based dosage forms (Ahmady and Abu Samah, 2021; Padhi et al., 2020). Furthermore, the buccal films can successfully ensure prolonged contact between the drug and the buccal epithelium due to the close interaction between the absorption site and the drug-rich surface of the film (Boddupalli et al., 2010; Sudhakar et al., 2006). The particular mucoadhesive properties of specific buccal films depend on the polymer/s employed (Bala et al., 2013; Ritu et al., 2014). Hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) are examples of cellulose derivatives that are usually adopted in the preparation of buccal films (Priyanka and Senthil Prabhu, 2020). Moreover, polymer concentration is an additional important parameter to consider when developing films with successful mechanical properties, drug loading capacity and disintegration times (Borges et al., 2015). From a technological point of view, films containing polymeric matrices are fabricated to be rapidly disintegrated in the mouth (Mfoafo et al., 2021). There are several examples of this technology applied to the administration of different molecules for children. Mucoadhesive buccal films based on chitosan blended with HPMC, methylcellulose (MC), HEC and polyvinyl alcohol (PVA), containing cetylpyridinium chloride demonstrated high antimicrobial activity against Streptococus mutans for the treatment of dental caries, gingivitis, aphthous ulcers and periodontitis (Abouhussein et al., 2020).

Similarly, a polymeric buccal film loaded with ondansetron hydrochloride, a selective inhibitor of the 5-HT3 receptor, is able to prevent and treat nausea and vomiting associated with postoperative cytotoxic chemotherapy and radiotherapy in the pediatric population (Trastullo et al., 2016). Furthermore, it was also found that bucco-adhesive films of gliclazide are suitable for the treatment of type II diabetes in children (Gaber et al., 2022). Moreover, a buccal film composed of ethanolic and aqueous films using sodium alginate (SA), HPMC, MC and carrageenan (CA), containing omeprazole have been developed (Khan et al., 2015). Additionally, propranolol hydrochloride has been loaded on a bi-layered buccal films formed by a blend of polyvinylpyrrolidone (PVP), PVA, chitosan and gelatin, with a back layer of insoluble ethylcellulose, to avoid the release of the drug in the oral cavity (Abruzzo et al., 2017). Ibuprofen (IB) is a nonsteroidal anti-inflammatory molecule conventionally used to reduce pain, fever and inflammatory deceases, such as rheumatoid arthritis (Rainsford, 2007). IB belongs to Class II of the biopharmaceutical classification system (BCS). It is a weak acid (pKa = 4.4) with water solubility of around 20 μg/mL (Park and Choi, 2006; Stoyanova et al., 2016) and for this reason it was selected as model drug. The formation of complexes with cyclodextrins (CDs) is a viable approach to enhancing IB solubility and release rate (Frömming and Szejtli, 1994; Hussein et al., 2007). This, in turn, has the potential to increase bioavailability (Argenziano et al., 2019; Argenziano et al., 2023; Di Cagno et al., 2011; Pereva et al., 2020; Yang et al., 2016).

Indeed, mucoadhesive buccal patches of IB have been proposed as a new therapeutic dosage form against buccal and dental diseases. The films were fabricated using the casting method with carboxymethylcellulose sodium salt (NaCMC) and PVP. The results show that no irritation occurred and that IB was detected in saliva for 5 h (Perioli et al., 2004). Similarly, Kianfar et al. (Kianfar et al., 2011) demonstrated that IB undergoes fast released from carrageenan- and poloxamer-based bioadhesive films). We propose the use of Linecaps®, a pea starch derivative consisting of linear and soluble amylose chains, containing α-helix structures (Fig. 1) that possess a hydrophilic external surface and a hydrophobic internal cavity able to complex lipophilic molecules showing taste-masking properties (Tannous et al., 2022). Linecaps® can be considered a “green” excipient, and its use might allow for the reduction of the amount of CD that present dose-limitation for pediatric use (EMA, 2017).

The objective of the present work is therefore the development of pediatric buccal films for poorly soluble drugs delivery using natural components in a solvent-free manufacturing process. We hypothesize that a new buccal drug delivery system can be obtained by exploiting a novel combination of biocompatible, natural-derived polysaccharides and cyclodextrins. The feasibility of exploiting this hydrophilic matrix for the fast release of poorly water-soluble molecules, such as IB, is here investigated. For the buccal film preparation, a solvent-free manufacturing process based on freeze-thaw technique was developed using a combination of HEC and Linecaps®. Furthermore, we suggest that a thin, flexible film might be a more acceptable dosage form for children, improving compliance. The study focuses on the in vitro film characterization, including physico-chemical and functional properties, mucoadhesion, and drug permeation behavior. The drug transmucosal uptake from the newly formulated film was investigated in vitro using both a synthetic biomimetic membrane and rabbit buccal mucosa, while additional biological evaluations (e.g. in vivo studies, antimicrobial and thrombogenic activity) can be addressed in future investigations.

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Materials

All solvents were HPLC grade. Methanol and ethanol were purchased from VWR Chemicals (BDH Prolabo®, Europe). IB, potassium dibasic phosphate, potassium dihydrogenphosphate, glycerol and sorbitol were obtained from Sigma-Aldrich (St. Louis, Missouri, USA). Deionized and MilliQ® water were produced using a Millipore system. Beta-cyclodextrin (β-CD) and KLEPTOSE® LINECAPS 17 pea maltodextrin (LC) by Roquette .

Greta Camilla Magnano, Anna Scomparin, Monica Argenziano, Rita Spagnolo, Elisabetta Muntoni, Dario Voinovich, Dritan Hasa, Valentina Bianchi, Ilaria De Munari, Roberta Cavalli, Exploring new buccal films based on hydroxyethyl cellulose and Linecaps® combination for the pediatric delivery of hydrophobic molecules, Carbohydrate Polymers, 2025, 124499, ISSN 0144-8617, https://doi.org/10.1016/j.carbpol.2025.124499.

See also our CPhI Frankfurt overview article: