Human mouthfeel panel investigating the acceptability of electrospun and solvent cast orodispersible films

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Abstract

A human panel study was performed to investigate the acceptability of orodispersible electrospun and solvent cast films. 50 healthy volunteers took two drug-free samples of polyvinyl alcohol films prepared by the two methods. On a 5-point hedonic scale, the volunteers assessed the films’ perceived size, stickiness, thickness, disintegration time, thickening effect on saliva, and handling. The films manufactured by both methods were similar in their end-user acceptability. The modal values of perceived size, thickness, disintegration time, saliva thickening effect, and handling were high (4 or 5). However, for both, the stickiness mode was 2 (strongly sticky) and the only negative attribute. Both films were reported to take approximately 30 s to disintegrate completely in the mouth. Electrospun films scored similarly high to solvent cast orodispersible films in most attributes of end-user acceptability. Electrospun films were marginally preferred, with 27 out of 50 participants picking electrospinning when presented with a forced choice test of both fabrication methods. This is the first study to show that electrospinning enables the fabrication of orodispersible films that are acceptable to adult human participants in terms of handling and mouthfeel and suggests that the potential for clinical translation of such formulations is high.

Introduction

Poor patient acceptability leads to low compliance with a dosage regimen. This can have a negative impact on treatment completion and clinical outcomes. Geriatric and paediatric patient populations have the most compliance issues owing to a lack of formulations matching their needs (Liu et al., 2014). The challenges that face those groups include issues with swallowing a solid dosage form, palatability problems, and error associated with intervention of a care-giver when administering a measured liquid dose (Borges et al., 2015, Vuddanda et al., 2016). Age-appropriate dosage forms offer a solution to these challenges (Lopez et al., 2015). Perhaps most importantly, these dosage forms should be palatable for the patient, with palatability being defined as the overall appreciation of a medicine’s properties, such as its appearance, smell, taste, mouthfeel and aftertaste (Walsh et al., 2014).

Orodispersible films (ODF) are excellent candidates for age-appropriate formulations. They are thin, easy to swallow, can be formulated to be taste-masked and do not require water to be taken (Hanning et al., 2016). They also offer flexible dosing, possess no risk of choking and offer improved dose accuracy in comparison to syrups, which renders them suitable for paediatric drug delivery (Bala et al., 2013). Oral films are suitable to be given to children, but key attributes such as stickiness, disintegration time and thickness need to be optimised to ensure maximum acceptability (Scarpa et al., 2017). One limitation of ODFs is the potential for low drug loading however, with a maximum of approximately 50 mg per film (Visser et al., 2020).

The most common route to ODF preparation is solvent casting, in which a polymer and drug are dissolved in a solvent, charged into a die, and then the solvent evaporated. There has been a limited amount of previous research comparing polymers and their molecular weights in terms of their effects on the acceptability attributes of solvent cast films. Scarpa et al. found that the chemical structure and molecular weight of a polymer influence stickiness perception, and the molecular weight has a major influence on disintegration time (Scarpa et al., 2018). They concluded that 39 kDa polyvinyl alcohol (PVA) shows acceptable mouthfeel properties, hence this grade was selected for use in this study.

Solvent casting has limitations, however. The number of polymers and solvents which can be used are limited. The process may sometimes require heat, and thus may be unsuitable for thermolabile excipients and active ingredients (Lade Milind et al., 2013). It also often requires the addition of excipients such as plasticizers to improve the formulation properties, for example to lower the glass transition temperature and thus improve the mechanical properties of the films. This can be especially undesirable for a dosage form intended to be used in the paediatric population (Garsuch and Breitkreutz, 2010). Paediatric dosage forms should include the minimum amount of excipients possible, as detailed in the European Medicines Agency (EMA) guidance document (EMEA, 2013). This is the case even for excipients which are generally recognized as safe (GRAS) in adults, because there is limited safety data on the effect of exposure to excipients on children’s developing organ systems.

Oral films can be produced by manufacturing methods other than solvent casting, such as by hot melt extrusion, rolling and electrospinning (Bala et al., 2013). The mechanical properties and plasticity of polymer films are influenced by the fabrication methods (Ghosal et al., 2018), and thus may also have an effect on mouthfeel acceptability. For instance, studies by Ghosal et al. (2018) showed that PVA films produced by solvent casting were brittle unless a high amount of glycerol was added, whereas electrospun films were more naturally flexible.

Electrospinning involves the preparation of a polymer solution in a volatile solvent (typically with a functional component present too), and the subsequent extrusion of this solution through a metal needle towards a metal collector plate. A high (kV) potential difference is applied between the two, which results in the formation of non-woven fibre mats on the collector. The latter have traditionally been used for wound healing (Grip et al., 2018) or as biomedical scaffolds (Meinel et al., 2012), but have also been explored for oral drug delivery (Abdelhakim et al., 2019, Balogh et al., 2018, Balogh et al., 2017, Celebioglu and Uyar, 2019, Domokos et al., 2019, Nitanan et al., 2013, Payab et al., 2014, Wu et al., 2015). Electrospinning as a fabrication technique has some inherent advantages; for instance, the non-woven mats produced have hugely increased surface area to volume ratios compared to traditional films, which can lead to faster dissolution (Williams et al., 2018). Electrospun formulations have been investigated for taste-masking (Samprasit et al., 2017, Samprasit et al., 2015), giving them potential for the production of age-appropriate formulations. Electrospinning also requires little to no addition of excipients, unlike solvent casting. Further, it does not require heat (in contrast to hot melt extrusion) therefore making it more suitable for application with a wider range of materials, particularly thermally labile drugs (Qi and Craig, 2015, Sergio Torres-Giner and Rocio Perez-Masia, 2016, Williams et al., 2012). The process can be scaled up to industrial production levels, with multiple companies now offering high throughput and GMP manufacture of electrospun products (Vass et al., 2019). However, while these advantages suggest that electrospinning may be a viable alternative in the preparation of ODFs, the question remains as to how patients will perceive films prepared in this manner. This is of fundamental importance for further development, as poor acceptability will undermine any performance advantages incurred by the nanofabrication approach.

In this study, the effect of the manufacturing method used to prepare ODFs on mouthfeel acceptability was explored. To do so, a human taste panel, the gold standard approach for assessing the palatability of a dosage form (Eckert et al., 2013, Soto et al., 2018), was designed and undertaken. Its aim was to assess the ability and willingness of healthy volunteers to self-administer placebo electrospun and solvent cast film formulations.

Section snippets

Ethics

This study was a single centre, single blinded cross-over study and was conducted at the UCL School of Pharmacy. The study design was approved by the UCL Research Ethics Committee (REC; project ID: 15975/001). All data were handled in line with the General Data Protection Regulation 2018.

Participant recruitment

An email was sent out to UCL School of Pharmacy staff and students to recruit them to the study. We sought healthy volunteers between 18 and 60 years of age. Smokers and individuals who had received dental care

Film characterisation

The electrospun films had a mass in the range of 22–26 mg, with a mean mass of 24.94 ± 1.04 mg. They were cut to 3 × 2 cm, with a thickness of 253 ± 10 µm (Fig. 2). The cast films were generated with an equivalent mass or 25.35 ± 1.40 mg, resulting in dimensions of 2 × 1.7 cm and a thickness of 83 ± 10 µm (Fig. 2). It is clear that the two formulations have different sizes and colours, which could impact acceptability attributes such as handling.

The films were imaged using SEM, with images

Conclusion

We report in this work the first study investigating the acceptability of electrospun orodispersible films. Placebo PVA films were prepared by solvent casting and electrospinning under GMP conditions and controlled to have equivalent mass but the latter was slightly bigger (3 × 2 cm vs 2 × 1.7 cm). A human panel comprising 50 healthy volunteers were asked to consider the thickness, size, disintegration time, handling, saliva thickening effect and stickiness of the formulations. The electrospun

CRediT authorship contribution statement

Hend E. Abdelhakim: Methodology, Formal analysis, Investigation, Writing - original draft, Visualization. Gareth R. Williams: Conceptualization, Resources, Writing - review & editing. Duncan Q.M. Craig: Resources, Writing - review & editing, Funding acquisition. Mine Orlu: Conceptualization, Methodology, Resources, Writing - review & editing, Supervision, Project administration, Funding acquisition. Catherine Tuleu: Methodology, Investigation, Resources, Writing - review & editing, Supervision.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

The mouthfeel evaluation study was funded by a UCL Grand Challenge of Transformative Technology Small Grant awarded to Dr Mine Orlu and Dr Ben Hanson (https://www.ucl.ac.uk/grand-challenges/news/2018/nov/grassroots-cross-disciplinary-research-supported-through-grand-challenges). Hend Abdelhakim is a PhD student funded by the Medical Research Council (iCASE award no. 170156) and Pfizer Ltd (award no. 173803).

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