Development of a hybrid tablet-integrated superporous hydrogel for gastro-retentive delivery of famotidine

Abstract

A gastro-retentive drug delivery system based on a tablet-integrated superporous hydrogel (SPH) was developed using Famotidine as a model drug for ulcer treatment. The objective of this study was to enhance gastric retention and sustained drug release, thereby improving the bioavailability of Famotidine, a BCS Class III drug with limited permeability and incomplete absorption. The SPH system was designed to retain the formulation in the upper gastrointestinal tract, the primary site of drug absorption, and was prepared using a gas-blowing (foaming) technique. A 3² full factorial design was employed to optimize the formulation by varying the concentrations of Crosspovidone and Cassia tora as independent variables. The developed SPH formulations were evaluated for porosity, swelling index, void fraction, water retention capacity, morphology, drug–excipient compatibility, and in vitro and in vivo drug release behaviour. The optimized formulation (F1) exhibited a high cumulative drug release of 98.2191 ± 0.06%, a swelling ratio of 297.2 ± 0.11%, void fraction of 0.4366 ± 0.015, porosity of 0.171 ± 0.07, and water retention time of 0.9552 ± 0.07 min. FTIR analysis confirmed the compatibility between Famotidine and excipients, while DSC studies indicated that the drug remained in its stable form without alteration during formulation. In vivo radiographic studies demonstrated that the optimized SPH formulation remained buoyant and retained in the stomach for up to 12 h, providing prolonged gastric residence and sustained drug release. Overall, the tablet-integrated SPH system represents an effective gastro-retentive approach for enhancing the therapeutic performance of Famotidine.

Introduction

Gastro-retentive drug delivery systems (GRDDS) represent an effective approach for reducing dosing frequency and improving patient compliance by prolonging drug residence time in the stomach [1–3]. Among various GRDDS platforms, superporous hydrogels (SPHs) have gained considerable attention due to their rapid swelling behaviour, high porosity, and ability to provide controlled drug release [4]. SPHs, also known as aqua gels, are cross-linked hydrophilic polymers possessing a three-dimensional network structure capable of absorbing large quantities of aqueous fluids and swelling extensively [5]. Drugs incorporated into the polymeric matrix are released as a consequence of hydrogel swelling and expansion. These hydrogels are characterized by interconnected pores ranging from the micron to millimeter scale, which facilitate rapid water uptake and uniform drug diffusion.

SPHs are commonly prepared using initiators, crosslinkers, and foaming agents in the presence of monomers [4]. The foaming mechanism results from a reaction between acids and carbonates, generating gas bubbles that create the porous structure within the hydrogel matrix. Second-generation SPHs, introduced as an advancement over conventional first-generation systems, exhibit improved mechanical strength and elasticity and are often referred to as superporous hydrogel composites (SPHCs) [6]. These systems incorporate composite agents or matrix swelling additives that enhance structural integrity and swelling capacity [7,8]. In the present study, second-generation SPHs were formulated using a gas-blowing (foaming) technique, wherein monomers were cross-linked around gas bubbles generated by sodium bicarbonate in an acidic medium.

Famotidine, a histamine H₂-receptor antagonist widely prescribed for the management of peptic ulcer disease, gastroesophageal reflux disease (GERD), and Zollinger–Ellison syndrome, was selected as the model drug [9,10]. Pharmacokinetically, famotidine is rapidly absorbed from the upper gastrointestinal tract, achieving peak plasma concentrations within 1–3 h following oral administration [11,12]. However, its absolute oral bioavailability is relatively low (approximately 40–45%) due to incomplete absorption, despite negligible hepatic first-pass metabolism. Additionally, famotidine has a short elimination half-life of 2.5–3.5 h, necessitating frequent dosing to maintain therapeutic efficacy [13,14]. Clinically, famotidine is available in conventional dosage forms such as immediate-release tablets, chewable tablets, oral suspensions, and injectable preparations [15,16]. These formulations are associated with limitations including rapid gastric emptying, short gastric residence time, and fluctuating plasma drug concentrations, which may compromise therapeutic outcomes and patient adherence.

Moreover, famotidine is classified as a Biopharmaceutics Classification System (BCS) Class III drug, characterized by high aqueous solubility but low intestinal permeability, making its absorption highly dependent on prolonged residence in the upper gastrointestinal tract [17]. To address these challenges, various formulation strategies—such as floating tablets, raft-forming systems, mucoadhesive formulations, microspheres, and hydrophilic matrix systems—have been investigated to enhance the gastric retention and bioavailability of famotidine [15,16]. Although these approaches have shown partial success, issues related to insufficient mechanical strength, uncontrolled swelling, and premature drug release remain unresolved. Therefore, the development of a robust and reliable gastro-retentive delivery system capable of sustained gastric retention and controlled drug release is still a significant formulation challenge. Structurally, famotidine is a thiazole-containing compound with a sulfamoyl group and a substituted guanidine moiety, features that confer high polarity and limited membrane permeability. Understanding its chemical structure is essential for rational formulation design, particularly when selecting polymers and matrix systems intended to modulate swelling behaviour release kinetics, and gastric retention. The structure of famotidine is depicted in Fig 1.

Fig 1. Chemical structure of famotidine.

Crospovidone, a commonly used super disintegrant in tablet formulations, was incorporated as a composite agent in the present GRDDS [18,19]. Although crospovidone itself is not retained in the stomach, its swelling property upon contact with gastric fluid can facilitate controlled disintegration and progressive drug release when combined with a gastro-retentive system. Such integration enables a more regulated release profile, which is advantageous for drugs with narrow absorption windows in the upper gastrointestinal tract [18,19].

Additionally, Cassia tora, a leguminous plant native to India, was employed as a natural polymer in the formulation. The mucilage derived from Cassia tora seeds is rich in galactomannan-type polysaccharides and exhibits strong hydrophilic, viscous, and bioadhesive properties, making it an effective swelling agent and matrix former [20–22]. In gastro-retentive drug delivery, Cassia tora contributes to enhanced water absorption, prolonged gastric residence time, and sustained drug release in the acidic gastric environment. Its low toxicity, biodegradability, and documented pharmacological activities further support its suitability for pharmaceutical applications [20–22].

In this study, a hybrid gastro-retentive system was developed in which a drug-loaded tablet plug was embedded within a superporous hydrogel matrix. The SPH serves as the primary platform for gastric retention and controlled drug release, while the tablet core enhances structural integrity and buoyancy. The developed GRDDS-SPH formulations were characterized using in vitro and in vivo evaluation methods, and a 3² full factorial design was employed to optimize the formulation variables for improved performance.

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Materials

Famotidine was obtained as a gift sample from Wockhardt Ltd., Aurangabad, Maharashtra, India. Crospovidone (pharmaceutical grade, Kollidon® CL) was procured from BASF India Ltd., Mumbai, India, and used as a composite agent. Cassia tora gum (pharmaceutical grade) was obtained from a Chem Pro Solutions, Mumbai 400063, Maharashtra, India, and used as a natural polymeric matrix former. N,N′-methylene bis acrylamide (BIS) and N,N,N′,N′-tetramethyl ethylenediamine were purchased from Loba Chemie Pvt. Ltd., Mumbai, India. Acrylic acid was obtained from Research-Lab Fine Chem Ltd., Mumbai, India. Magnesium stearate (pharmaceutical grade), used as a lubricant in tablet formulation, was procured from Loba Chemie Pvt. Ltd., Mumbai, India. All other chemicals and excipients used in the study were of analytical or pharmaceutical grade and were used as received.

Thombre N, Chandramore K, Tajanpure A, Al Fatease A, Hani U, Alamri AH, et al. (2026) Development of a hybrid tablet-integrated superporous hydrogel for gastro-retentive delivery of famotidine. PLoS One 21(5): e0347426. https://doi.org/10.1371/journal.pone.0347426