Modification of the Biorelevant Release Testing of Esophageal Applied Mucoadhesive Films and Development of Formulation Strategies to Increase the Mucosal Contact Time

Introduction

The number and prevalence of esophageal diseases such as gastroesophageal reflux disease (GERD), eosinophilic esophagitis (EoE), Barrett’s esophagus and esophageal cancer have increased significantly in recent years [1,2,3]. To meet the challenges of therapy, such as in the case of EoE, the long-lasting local application of active substances at the site of the disease is a key factor for success [4,5]. The particularly short transit times of oral dosage forms, which range from 7 to 14 s depending on type, viscosity, amount and body position, pose a major challenge [6,7]. Novel delivery systems, such as the EsoCap concept, which has already been successfully tested in a phase II clinical trial, are intended to enable prolonged drug delivery in the esophagus through the local application of a mucoadhesive film that forms a viscous gel upon swelling [8,9].

To assess the biorelevant release behaviour of newly developed films for esophageal application, a biorelevant dissolution model was developed with the so-called EsoPeriDiss, which can simulate the flow rate, inclination and peristalsis of the esophagus [10,11]. The anatomy and physiology of the esophagus, an approximately 25 cm long collapsed muscular tube, was simulated for this purpose [12]. A healthy adult swallows between 100 and 600 times a day, with one-third of swallows being due to the ingestion of food or drink, which triggers a primary peristaltic wave [13,14]. Less than 10% of swallows occur at night [15]. The peristaltic wave propagates as a contractile wave with a velocity of 2–6 cm/s in the distal esophagus. In addition, involuntary secondary peristalsis may be triggered, e.g., as a self-cleaning reflex of the esophagus [16]. A large part of the daily swallowing act is accounted for by basal salivary secretion, which ranges from 500–2500 mL per day and is mainly due to the three paired salivary glands. In addition, there are other small salivary glands in the submucosal layer of the esophagus which are more prominent in the upper and lower parts of the esophagus and produce saliva containing bicarbonate, e.g., for acid resistance [17]. The small glands and the sublingual gland are purely mucous glands that produce a mucin-rich secretion. Together they are responsible for 80% of the daily mucin production. In addition, saliva is 97–99% water, in which electrolytes, lipids and glycoproteins are dissolved [15,18]. Ionic components include phosphate and bicarbonate, which contribute to the buffering capacity of saliva, as well as sodium, potassium, magnesium, zinc, calcium, chloride, fluoride, iodide and nitrate. The protein fraction consists of enzymes such as amylase and lipase, as well as albumin, immunoglobulins and mucins, which also influence the viscosity of the saliva. As the amount of secretion increases, so does the secretion of bicarbonate and sodium ions, raising the pH of the saliva. In the literature, the pH of basal saliva is reported to be 5.8, while the pH of stimulated saliva is reported to be 7.6 [19,20].

The aim of this work was to further develop the existing model for biorelevant simulation of the esophagus [10,11]. One focus was to establish the temperature control of the model and the medium. In addition, the release behaviour of different film thicknesses and polymer qualities, in combination with highly and poorly soluble model drugs, was to be estimated and investigations with artificial saliva were to be carried out.

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Materials

Various grades of polyvinyl alcohol, such as PVA 4-88, 8-88, 18-88 and 26-88 of the Emprove Essential series, were kindly provided by Merck (Darmstadt, Germany). Glycerol as plasticiser for the films was purchased from Caelo (Hilden, Germany) and demineralised water was used as solvent. Fluorescein sodium was purchased from Sigma-Aldrich Chemie (Darmstadt, Germany) and riboflavin from Fagron GmbH & CoKG (Barsbüttel, Germany). Potassium dihydrogen orthophosphate was obtained from neoFroxx GmbH (Einhausen, Germany) and sodium hydroxide was purchased from AppliChem GmbH (Darmstadt, Germany). For the preparation of artificial saliva, xanthan from VWR Chemicals (Radnor, PA, USA), mucin from Carl Roth GmbH & Co. KG (Karlsruhe, Germany), Tween 20 from Sigma-Aldrich Chemie GmbH (Steinheim, Germany), sodium hydrogen phosphate from neoLab Migge GmbH (Heidelberg, Germany) and anhydrous citric acid from Caesar & Loretz GmbH (Hilden, Germany) were used.

Brokmann, F.; Simonek, P.; Rosenbaum, C. Modification of the Biorelevant Release Testing of Esophageal Applied Mucoadhesive Films and Development of Formulation Strategies to Increase the Mucosal Contact Time. Pharmaceutics 2024, 16, 1021. https://doi.org/10.3390/pharmaceutics16081021

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