Hot Melt Extrusion as Continuous Manufacturing Technique to Produce Bilayer Films Loaded with Paracetamol or Lactase

Abstract

Background/Objectives: The oral delivery of large-molecule drugs remains challenging due to poor solubility, perdemeability, and stability in the gastrointestinal tract, resulting in low bioavailability. In this study, hot melt extrusion (HME) was investigated as a solvent-free manufacturing technique for mucoadhesive bilayer films to improve drug absorption.

Methods: Polyvinyl alcohol (PVA) and polyethylene oxide (PEO) were evaluated as mucoadhesive film-forming polymers, in conjunction with Eudragit^® RS as a water-insoluble backing layer. Paracetamol and lactase were utilized as small and large molecule APIs, respectively. The resulting films were assembled into bilayer film samples and examined for mechanical properties, mucoadhesion, and dissolution behavior. A novel dissolution model was developed to evaluate unidirectional drug transport.

Results: The results showed that bilayer films could be successfully fabricated using HME, with different mechanical properties depending on the polymer and drug content. Tests with the newly developed dissolution model showed a unidirectional drug release. The model also confirmed the need for biorelevant dissolution test systems because of a better differentiation between polymers compared to standard test methods such as the paddle-over-disk method. Furthermore, the investigation revealed that the activity of enzymes was retained after extrusion, thus indicating the feasibility of processing biologics.

Conclusions: This study highlights the potential of HME to produce bilayer films as an innovative drug delivery platform offering improved bioavailability for both small and large molecules.

Introduction

The design of drug delivery systems plays a crucial role in overcoming the biopharmaceutical challenges associated with delivering drug compounds to their targeted site in the human gastrointestinal tract (GIT). Oral administration remains the most common route, with the small intestine typically serving as the primary site of absorption. However, the effective delivery of large molecules, which are a key focus in modern drug therapy, presents significant challenges due to their solubility, permeability, and stability in the GIT [1,2,3].

The small intestine functions as a complex barrier that active pharmaceutical ingredients (APIs) must overcome to enter systemic circulation [4,5,6]. Consequently, large molecules often exhibit very low bioavailability, as only a small fraction of the administered drug reaches blood circulation. To address this issue, various formulation strategies have been explored, including emulsifying systems and nanoparticles, aimed at enhancing bioavailability [7]. Hetényi et al. found that self-emulsifying drug delivery systems (SEDDS) offer good protection for peptides against intestinal protease degradation [8]. It could also be proved that SEDDS with insulin have an effect on blood glucose levels in rats, and permeability could be demonstrated with a cell monolayer assay [9]. Besides emulsifying systems, mucoadhesion is another option to improve absorption and therefore bioavailability [10]. In pharmaceutical technology, hydrophilic polymers are often used to achieve mucoadhesivity. Also, groups of polymers that possess charged groups or non-ionic functional groups have mucoadhesive characteristics [10]. These polymers are used within a variety of different dosage forms [11,12,13]. Especially the administration of films in the upper parts of the GIT (oral cavity or esophagus) is very convenient and, in most cases, with training, easy to handle for patients [14]. Films offer the advantage of delivering variable amounts of drugs and different types of active substances for either local or systemic drug delivery. Many film-based drug formulations have already been developed and tested in clinical trials or have been marketed [12,15]. A main challenge is the incorporation of large molecules in film-based drug delivery systems. Factors such as absorption or stability need to be considered in the process of drug formulation development. Films can be manufactured by the solvent-casting (SC) technique, which is one of the most widely used techniques. It offers the advantage of easy handling, preparation of very thin films, and low costs. On the contrary, poor content uniformity because of self-aggregation can be problematic as well as the required use of organic solvents [16,17]. Another manufacturing technique is hot melt extrusion (HME). In comparison to SC, HME is a continuous manufacturing process and does not require solvents during the process. This can be of advantage for possible upscaling. However, HME involves heat as a potentially critical parameter.

SC and HME have in common that the structure of the protein or peptide drug might change to an energetically more favorable form, and at the same time, it loses its functionality [18]. In the past researchers could show that folding of proteins depends on the protein dynamical temperature and can be influenced by the addition of stabilizers such as glycerol [19,20]. This points out the potential use of HME for drug delivery of proteins in films. Different approaches for delivering macromolecules to the site of application have been made in the past. Jørgensen et al. developed a self-unfolding foil loaded with insulin which is intended to apply the active ingredient in the small intestine [21]. Gu et al. manufactured a biodegradable thin film with incorporated siRNA-loaded nanoparticles for intravaginal application [22]. Although both works did not include HME in the manufacturing process, they are examples for the successful use of large molecules in films. To protect large molecules from degradation processes a backing layer could be attached to mucoadhesive films. This layer would provide not only a unidirectional drug transport but also a comparably high local drug concentration which could lead to better absorption. Abruzzo et al. manufactured bilayer films with ethyl cellulose as the backing layer with SC and compared the permeability with monolayer films [23]. They found that adding the backing layer increased the permeation of the drug.

This work will pursue two objectives. Firstly, a bilayer film was manufactured with HME, and the single layers as well as the bilayer films were characterized and tested for drug release behavior. For improving the manufacturing process, paracetamol was used as a model drug in the beginning. Secondly, an enzyme as model drug was used for preparing a mucoadhesive film with HME and was also characterized and tested for enzyme activity.

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Materials

Polyvinyl alcohol Parteck MXP 4-88 and 18-88 (Emprove Essential, PVA), triethyl citrate, and β-galactosidase from aspergillus oryzae were provided by Merck KGaA (Darmstadt, Germany). Glycerol anhydrous, propylene glycol, paracetamol, calcium chloride dihydrate, and sodium chloride were purchased from Caesar and Loretz GmbH (Hilden, Germany). Triethyl citrate (TEC) and sodium hydroxide were supplied by AppliChem GmbH (Darmstadt, Germany). Eudragit® RS PO was purchased from Evonik Röhm GmbH (Darmstadt, Germany). Agar was provided by Sigma-Aldrich Chemie GmbH (Steinheim, Germany). Fumed silica was supplied by Fagron GmbH & Co. KG (Glinde, Germany); mucin (from porcine stomach mucosa), magnesium sulfate heptahydrate, potassium chloride, and HEPES were purchased from Carl Roth GmbH + Co. KG (Karlsruhe, Germany). Polyethylene oxide (Polyox WSR N10 (PEO N10), Polyox WSR N80 (PEO N80)) was kindly provided by DuPont de Nemours GmbH (Neu-Isenburg, Germany). Lactase in the form of commercial lactase capsules (Lactrase® 12000 FCC, capsules) was purchased from Pro Natura Gesellschaft für gesunde Ernährung mbH (Bad Vilbel, Germany). o-nitrophenyl-β-d-galactopyranoside (ONPG) was supplied by ThermoFisher GmbH (Karlsruhe, Germany).

Brokmann, F.; Luthe, K.; Hartmann, J.; Müller, L.; Klammt, F.; Hoffmann, C.; Weitschies, W.; Rosenbaum, C. Hot Melt Extrusion as Continuous Manufacturing Technique to Produce Bilayer Films Loaded with Paracetamol or Lactase. Pharmaceuticals 2025, 18, 310. https://doi.org/10.3390/ph18030310

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