In Silico Preformulation Modeling, Solubility Enhancement, and Sustainable Release of Rebamipide Utilizing Deep Eutectic Mixture Loaded Bioadhesive Controlled Release Granules for Gastritis Treatment

Abstract

Background/Objectives: Rebamipide is a gastroprotective agent with poor aqueous solubility and rapid gastrointestinal clearance, leading to reduced therapeutic efficiency. This study aimed to enhance the solubility, mucoadhesion, and sustained oral delivery of Rebamipide through the development of a deep eutectic mixture (DEM)-based bioadhesive controlled-release granule formulation.

Methods: In silico hydrogen-bonding interactions between Rebamipide, malonic acid, and urea were analyzed using CCDC tools. A thermodynamically stable DEM (1:3:1) was prepared and incorporated into bioadhesive granules using chitosan and HPMC. Physicochemical characterization was conducted using FTIR, DSC, TGA, and PXRD. Solubility, in vitro dissolution, ex vivo mucoadhesion (sheep gastric mucosa), and in vivo gastric retention (BaSO₄-loaded granules in rats) were evaluated.

Results: The optimized DEM significantly enhanced Rebamipide solubility (10.08 mg/mL vs. 0.045 mg/mL). Solid-state analyses confirmed hydrogen-bond formation and reduced crystallinity. DEM granules exhibited sustained drug release over 24 h (99.7 ± 0.8%) with improved dissolution efficiency compared to the marketed tablet (Mucosta®, 100 mg; T₅₀%: 5.03 h vs. 0.82 h). Kinetic modeling indicated non-Fickian anomalous transport (n = 0.47). The bioadhesive force of DEM granules (0.29 ± 0.02 N) was significantly higher than that of the pure drug and physical mixture. In vivo radiographic studies confirmed prolonged gastric retention.

Conclusions: The DEM-based bioadhesive granule system effectively improves solubility, dissolution rate, mucoadhesion, and gastric retention of Rebamipide. This approach represents a promising platform for once-daily gastroretentive oral delivery, pending further pharmacokinetic evaluation.

Introduction

Gastritis, one of the most prevalent gastric inflammatory diseases, can lead to serious complications if there is no timely diagnosis and treatment. Proper therapy requires an effective targeted therapy approach [1]. Unfortunately, many drugs offer limited effective therapy because of their solubility and rapid gastric clearance [2]. Rebamipide, a gastroprotective and anti-inflammatory cytoprotective agent, demonstrates low bioavailability because of limited aqueous solubility, thus hindering localized gastric therapy [3].

In recent years, advanced drug delivery systems have sought to optimize drug formulations to achieve greater therapeutic outcomes in drug solubility and gastric retention. Of these, deep eutectic mixtures (DEMs) have increasingly gained attention for their ability to enhance solubility in poorly soluble therapeutics [4]. The present study utilized a novel DEM of urea and malonic acid to achieve greater solubility of Rebamipide. The solubilization mechanism was explained using hydrogen bond interaction data from the CCDC, which demonstrated the existence of strong and thermodynamically favorable hydrogen bonds between the drug and the eutectic components [5]. The selection of urea and malonic acid as DEM components was based on several formulation and mechanistic considerations. Both materials are pharmaceutically acceptable and possess well-established hydrogen-bond donor–acceptor properties that favor eutectic formation with poorly soluble drugs. Urea is a bifunctional molecule containing NH2 donor groups and a carbonyl acceptor group, enabling versatile intermolecular interactions with Rebamipide functional groups such as phenolic OH, amide NH, and carbonyl oxygen atoms. Malonic acid was selected because its dicarboxylic structure provides a higher density of hydrogen-bonding sites than monocarboxylic acids such as acetic acid or lactic acid, thereby increasing the likelihood of forming a cooperative hydrogen-bonding network capable of destabilizing the crystalline lattice of Rebamipide. Compared with other commonly reported eutectic-forming materials such as choline chloride, citric acid, or nicotinamide, the urea–malonic acid combination was considered more suitable for the present system because it offers a balanced combination of strong intermolecular interaction potential, good miscibility, and mild processing requirements. In addition, both components can form eutectic systems at relatively low temperatures (60–70 °C), which minimizes the risk of thermal degradation of Rebamipide during preparation. Thus, the selection of these two components was guided not only by availability and safety, but also by their expected ability to maximize hydrogen-bond-mediated solubilization and amorphization of the drug.

Other than enhancing solubility, mucoadhesive controlled-release granules containing HPMC (hydroxypropyl methylcellulose) and chitosan were developed to sustain drug release and extend gastric residence time [6]. These polymers possess desirable adhesive and swelling properties, which are essential in maintaining the localization of the drug in the gastric environment [7]. Mercury and Conquest™ software suite provided guidance for in silico preformulation modeling, which helped in rational mechanistic formulation development [8]. This modeling provided information on pre-simulated gastrointestinal, solubility, and absorption, dissolution, and absorption geometry, and dissolution and absorption kinetics. The combination of rational mechanistic development and empirical data from CCDC formulates the development from a rational mechanistic perspective [9]. The developed strategy in this study is the use of hydrogen bond solubilization and gastric retention. This introduces a scalable and mechanistically grounded approach for potentially improving the oral bioavailability of Rebamipide, pending formal pharmacokinetic confirmation. The outcomes not only contribute to the improved management of gastritis but also provide a platform for addressing solubility challenges in other BCS Class II/IV drugs using DEM-based and mucoadhesive technologies.

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2.1. Materials

Rebamipide (purity ≥ 98%) was kindly supplied by Koye Pharmaceuticals Pvt. Ltd. (Mumbai, India). Sigma-Aldrich (St. Louis, MO, USA) provided the malonic acid (purity ≥ 98%) and urea (analytical grade, ≥99%). The supplier of hydroxypropyl methylcellulose (HPMC, K100M grade) was Colorcon Asia Pvt. Ltd. (Goa, India), and chitosan was obtained from Lubrizol Advanced Materials Inc. (Cleveland, OH, USA). Ethanol (absolute), methanol (HPLC grade), potassium dihydrogen phosphate (KH₂PO₄), sodium hydroxide pellets, and additional analytical-grade reagents and solvents used in this research were gifted by Pioneer Company for Scientific Supplies, Sulaymaniyah, Iraq. The commercially available Rebamipide product used as a comparator in dissolution studies was Mucosta^® tablets (100 mg Rebamipide per tablet; Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan), purchased from a licensed local pharmacy. Each tablet was used as supplied, without further modification, and an amount equivalent to 100 mg Rebamipide was employed per dissolution run to ensure equivalent dose comparison with the prepared DEM granules. Chemical structures were drawn using ChemDraw software (version 20.0, PerkinElmer Informatics, Waltham, MA, USA). DDsolver (Microsoft Excel add-in, version 1.0) was used for in vitro release modeling and analysis. ConQuest (v2.0.5, CCDC, Cambridge, UK) and Mercury (v4.3.0, CCDC, Cambridge, UK) software were used for Hydrogen bond computation prediction. GraphPad Prism (version 9.0, GraphPad Software, San Diego, CA, USA) was used for statistical analysis.

Almajidi, Y.Q.; Al-Hakeem, M.A.; Yaseen, A. In Silico Preformulation Modeling, Solubility Enhancement, and Sustainable Release of Rebamipide Utilizing Deep Eutectic Mixture Loaded Bioadhesive Controlled Release Granules for Gastritis Treatment. Pharmaceutics 2026, 18, 521. https://doi.org/10.3390/pharmaceutics18050521

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