Electrospinning of pullulan-based orodispersible films containing sildenafil

Feasibility of electrospinning in the manufacturing of sildenafil-containing orodispersible films (ODFs) intended to enhance oxygenation and to reduce pulmonary arterial pressure in pediatric patients was evaluated. Given the targeted subjects, the simplest and safest formulation was chosen, using water as the only solvent and pullulan, a natural polymer, as the sole fiber-forming agent. A systematic characterization in terms of shear and extensional viscosity as well as surface tension of solutions containing different amounts of pullulan and sildenafil was carried out. Accordingly, electrospinning parameters enabling the continuous production, at the highest possible rate, of defect-free fibers with uniform diameter in the nanometer range were assessed. Morphology, microstructure, drug content and relevant solid state as well as ability of the resulting non-woven films to interact with aqueous fluids were evaluated. To better define the role of the fibrous nanostructure on the performance of ODFs, analogous films were produced by spin- and blade-coating and tested. Interestingly, the disintegration process of electrospun products turned out to be the fastest (i.e. occurring within few s) and compliant with Ph. Eur. and USP limits, making relevant ODFs particularly promising for increasing sildenafil bioavailability, thus lowering its dosages.

In the last decades, the implementation of innovative manufacturing processes in the pharmaceutical field has represented a promising development strategy, especially at the research level. Indeed, such an approach was demonstrated useful not only to reduce production costs, but also to favor the development of drug delivery systems (DDSs) having unique design and performance characteristics. This was the case of hot melt extrusion, injection molding, 3D and 4D printing as well as of electrospinning [Andreadis et al., 2022, Kallakunta et al., 2019; Madruga et al., 2022; Melocchi et al., 2021, Sarabu et al., 2019, Zema et al., 2012, 2017]. Notably, the latter process is driven by a high voltage electric field that, starting from polymeric solutions, suspensions and melts, enables the fabrication of an inter-connected web, often named as non-woven mat, composed of long and uniform micro- and nanofibers [Cleeton et al., 2019; Laudenslager et al., 2012; Ramakrishna et al., 2005]. The electrospinning technology stands out for its ease of operation, cost-effectiveness as well as scalability and, if coupled with suitable downstream processing, for being compatible with continuous manufacturing approaches [Guo et al., 2022, Persano et al., 2013, Si et al., 2023]. Although the production rate relevant to a lab-scale electrospinning apparatus is generally limited (around 0.01–1 g/h), higher values (even around 450 g/h) could be attained by using equipment provided with either multiple needles working in parallel or rotating spinnerets characterized by the presence of orifices in place of needles, thus being able to continuously stretch and elongate the liquid jet [Nagy et al., 2015, Omer et al., 2021; Vass et al., 2020]. Resorting to an additional air flow, as done in electroblowing, could provide further advantages, speeding up the solvent evaporation process. More recently, free-surface high-speed electrospinning technologies, even combined with centrifugal methods, were proposed and turned out compatible with large scale production standards (e.g. Nanospider™ by Elmarco).

Given the reduced diameter and high surface-to-volume ratio the resulting fibers are provided with, electrospinning has been tested in many different areas, such as biosensors, water filtration and wound dressings [Hassan et al., 2020; Luraghi et al., 2021, Xu et al., 2023, Zhan et al., 2022]. When applied to pharmaceutics, this technique was mainly employed for targeting bioavailability improvement of poorly-soluble drugs and manufacturing of biodegradable systems intended for transdermal delivery, implantation or tissue regeneration [Ignatova et al., 2013, Kumar et al., 2021, Meinel et al., 2012]. Indeed, the similarity between the structure of electrospun fibers (e.g. diameter, porosity) and that of the natural fibrillary extracellular matrix turned out to facilitate attachment and proliferation of cells [Doostmohammadi et al., 2020, Gao et al., 2019]. In the last years, feasibility of this technique for processing of biologics, such as enzymes, peptides and proteins, was also approached, resulting a viable alternative to traditional drying methods involving temperature increase, especially for heat-sensitive molecules [Blakney et al., 2013, Gizaw et al., 2018, Hu et al., 2020, Liu et al., 2022, Park et al., 2018, Vass et al., 2020a].

Overall, in most of the above-mentioned applications, the resulting non-woven mat underwent a milling step leading to the achievement of a powder, which was then used as the starting material for more traditional pharmaceutical processing (e.g. tableting, extrusion) [Démuth et al., 2015, Vass et al., 2020b]. In this respect, a few research groups are currently working on different downstream processes, entailing for instance folding/rolling of the non-woven mat followed by relevant cutting in the desired size. Alternatively, the electrospun fibers can be directly deposited onto an elongated rod that is subsequently moved to a die, in the cavity of which the mat is removed from the rod, compressed and ejected.

In view of their high surface area, non-woven mats attained by electrospinning were deemed interesting to be used as such as orodispersible films (ODFs) for oral administration of drugs [Balusamy et al., 2020, Ignatious et al., 2010, Nagy et al., 2010]. Indeed, by resorting to die-cutting, the mat could be simply divided into pieces of the selected size, the latter representing the final dosage form and containing the desired strength of the drug of interest.

Overall, ODFs appear as strips of thin polymeric layers to be placed onto the tongue and are intended to disintegrate/dissolve almost instantaneously in the saliva, thus not requiring water or swallowing [He et al., 2021a, Hoffmann et al., 2011, Preis et al., 2013]. Thanks to this unique behavior, they may enhance therapy adherence in the case of pediatric and geriatric subjects, as well as of people affected by dysphagia, Parkinson’s disease or mucositis [Scarpa et al., 2017; Slavkova et al., 2015]. Being the active ingredient expected to dissolve quickly, ODFs might also provide a faster onset of action and improved bioavailability with respect to other oral products. Indeed, if drug absorption mainly occurs through the oral mucosa, first-pass metabolism would be prevented [Ferlak et al., 2023, Visser et al., 2017]. In addition, ODFs are known to provide accurate and flexible dosing, being in principle able to fulfil the raising needs of precision medicine. So far, they were mainly fabricated by either sol-vent casting and hot melt extrusion but, more recently, preliminary data on their feasibility via 3D printing were also collected [Gupta et al., 2021, Khalid et al., 2021a, Khalid et al., 2021b, Musazzi et al., 2020]. When applied to ODFs manufacturing, the electrospinning process could lead to products with intrinsic high porosity, so as with improved performance, while avoiding the need for post-processing steps, such as drying or cooling, thus containing overall production costs [Kean et al., 2023].

Independent of the manufacturing process considered, film-forming polymers are essential components of ODFs. In the last years, new materials, for instance derived from the food industry, has started to be considered, with particular attention towards gluten-free, preservative-free polymers of vegetable origin [Garsuch et al., 2010; George et al., 2019, Ngwuluka et al., 2014]. In this respect, pullulan could represent an interesting candidate [Badhwar et al., 2018; Leathers et al., 2003; Singh et al., 2017]. It is a linear homopolysaccharide, synthesized by a yeast-like fungus through a fermentation process, and consists in maltotriose units (i.e. three glucoses connected by α-1,4 glycosidic bonds) linked to each other by an α-1,6 glycosidic bond. Such a peculiar pattern provides this polymer with high structural flexibility and enhanced solubility characteristics. Moreover, pullulan shows good adhesive properties and is able to form strong, oxygen impermeable films. While electrospinning potential of pullulan have started to be investigated especially in food packaging, only few similar studies were carried out in the drug de-livery field and even less targeted the production of ODFs [Chachlioutaki et al., 2020, Ponrasu et al., 2021, Qin et al., 2019, Sun et al., 2012]. In these articles, pullulan was mainly proposed as an electro-spinnability adjuvant, being able to raise the viscosity of the feedstock formulations based on other polymers, while lowering relevant conductivity as well as surface tension.

Based on these premises, the aim of the present work was to preliminarily evaluate the feasibility of electrospinning in the manufacturing of pullulan-based ODFs intended for the administration of sildenafil to pediatric patients. Indeed, sildenafil was recently proven useful in the treatment of persistent pulmonary hypertension in newborns and children, improving oxygenation index and pulmonary arterial pressure [Dhariwal et al., 2015; Evers et al., 2021, He et al., 2021b, Li et al., 2021, Zhang et al., 2020]. In this respect, oral administration of 0.1 to 0.5 mg/kg every 8 h was recommended, eventually customizing the dosing regimen based on therapy response [Abman et al., 2015]. However, the drug is subjected to a marked first-pass metabolism and for this reason would benefit greatly from buccal absorption [Nichols et al., 2002]. Given the targeted patients, the use of a natural polymer was considered essential, spinning adjuvants were avoided and water was selected as the only solvent. A systematic evaluation of pullulan-based placebo and drug-containing formulations to be electrospun was first carried out, followed by the selection of appropriate processing conditions and the manufacturing of ODF prototypes to be characterized.

Excipient used in the research beside others: Pullulan

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Elisabetta Ravasi, Alice Melocchi, Alessia Arrigoni, Arianna Chiappa, Chiara Grazia Milena Gennari, Marco Uboldi, Chiara Bertarelli, Lucia Zema, Francesco Briatico Vangosa, Electrospinning of pullulan-based orodispersible films containing sildenafil, International Journal of Pharmaceutics, 2023, 123258, ISSN 0378-5173,
https://doi.org/10.1016/j.ijpharm.2023.123258.