Developing a Chitosan/polyvinyl alcohol hydrogel for gastro-retentive release of ranitidine and enhanced anti-ulcerative properties

Abstract

Ranitidine is widely used to treat gastrointestinal conditions, but recent studies have revealed severe potential side effects, including a link to cancer. Therefore, this study aims to develop a new gastro-retentive formulation of ranitidine by utilizing the biocompatibility and biodegradability of Chitosan, along with the strength and hydrophilicity of polyvinyl alcohol (PVA). A chitosan/PVA/ranitidine hydrogel was created using the freeze-thaw method and evaluated for stability, ranitidine release behavior, and efficacy in treating ulcers in rats compared to a commercial formulation. The hydrogel demonstrates an average particle size of 69 nm, a polydispersity index of 0.344, and a zeta potential of + 38 mV. Transmission Electron Microscopy confirmed the spherical shape of the formulation, while X-ray diffraction verified its crystalline structure. Additionally, the study observed an impressive encapsulation efficiency of 98.66% ± 1.01 and a high drug content of 49.82% ± 1.29, as confirmed by Fourier transform infrared analysis. The prepared hydrogel controls the release of ranitidine over 12 h, with an average release of 87.98% ± 4.01%. The hydrogel exhibits minimal degradation over 15 days, greater thermal stability than ranitidine, and adequate stability in acidic gastric conditions. Furthermore, the cytotoxicity assay demonstrated that the hydrogel is biocompatible and promotes cell growth. The study discovered that the hydrogel formulation enhances the effects of ranitidine, particularly its antioxidant and anti-inflammatory properties. In vivo studies illustrated the hydrogel’s promising ulcer-healing properties, suggesting potential use in treating peptic ulcers. Hence, the chitosan/PVA hydrogel can be used as a possible drug delivery system for the sustained release of ranitidine.

Keywords: Chitosan; Gastric ulcer; Gastro-retentive drug delivery; Hydrogel; Ranitidine.

Fig. 1

Physicochemical characterization of Chitosan/PVA hydrogel containing ranitidine using dynamic light scattering technique, a transmission electron microscope (TEM) and UV spectra analysis. (a) Particle size distribution of Chitosan/PVA hydrogel containing ranitidine using dynamic light scattering technique demonstrating an apparent particle size of 69 nm. (b) Zeta potential of Chitosan/PVA hydrogel containing ranitidine. (c) TEM image showing the spherical shape of Chitosan/PVA hydrogel containing ranitidine. (d) UV–visible absorption spectra of Chitosan/PVA hydrogel containing ranitidine

Fig. 2

Structural Chitosan/PVA/Ranitidine hydrogel characterization using Fourier transform infrared (FT-IR)

Fig. 3

X-ray diffraction pattern for the crystalline structure of (a) Ranitidine sample and (b) Chitosan/PVA/Ranitidine hydrogel

Fig. 4

The encapsulation efficiency (EE%) and drug loading capacity (LC%) of Chitosan/PVA hydrogel containing ranitidine. Values are expressed as the mean of three replicate determination ± SEM

Fig. 5

Swelling degree of Chitosan/PVA hydrogel containing ranitidine at different pH of bicarbonate buffer solution. Values are expressed as the Mean of three replicate determinations ± SEM

Fig. 6

Gradual weight loss (%) of Chitosan/PVA hydrogel containing ranitidine in PBS at 37 ^◦C. Values are expressed as the mean of three replicate determinations ± SEM

Fig. 7

Moisture retention capability at different time intervals of Chitosan/PVA hydrogel containing ranitidine. Values are expressed as means of three replicate determinations ± SEM

Fig. 8

The in vitro release behavior of Ranitidine and Chitosan/PVA/Ranitidine hydrogel. Values are expressed as the means of three replicate determinations ± SEM

Fig. 9

Thermal stability of Ranitidine and Chitosan/PVA/Ranitidine hydrogel using Thermal gravimetric analysis (TGA)

Fig. 10

Stability of Ranitidine and Chitosan/PVA/Ranitidine hydrogel at different pH. Values are expressed as the means of three replicate determinations ± SEM

Fig. 11

Stability of Chitosan/PVA/Ranitidine hydrogel during in vitro simulated gastrointestinal digestion. Values are expressed as the means of three replicate determinations ± SEM

Fig. 12

Cytotoxicity of Ranitidine and Chitosan/PVA/Ranitidine hydrogel. (a) Micrographs of CCL-81 cell line treated with Ranitidine and Chitosan/PVA/Ranitidine hydrogel at 500 µg/ml. (b) The Viability percentage of the CCL-81 cell line against ranitidine and chitosan/PVA/ranitidine hydrogel at different concentrations. (c) IC₅₀ values of Ranitidine and Chitosan/PVA/Ranitidine hydrogel. Values are expressed as the means of three replicate determinations ± SEM

Fig. 13

In vitro biological activities of Ranitidine and Chitosan/PVA/Ranitidine hydrogel. (a) DPPH radical scavenging activity of Ranitidine and chitosan/PVA/Ranitidine hydrogel. (b) Stabilization percentage of RBC membrane by Ranitidine and chitosan/PVA/Ranitidine hydrogel at different concentrations. Values are expressed as the means of three replicate determinations ± SEM

Fig. 14

Gross morphological change of gastric mucosa. (a) The normal control group had a normal gastric mucosa with no signs of hemorrhagic lesions or ulceration. (b) Ulcerated rats displayed extensive and severe hemorrhagic gastric mucosal lesions. (c) Ulcerated rats treated with Ranitidine showed fewer hemorrhagic lesions of the gastric mucosa. (d) Ulcerated rats treated with Chitosan/PVA hydrogel showed a slight recovery. (e) Ulcerated rats treated with Chitosan/PVA/Ranitidine hydrogel showed a marked recovery with no hemorrhagic bands or injuries. (f) Gastric severity score of different ulcerated groups. Values are expressed as mean ± SEM (n = 6). Values with different superscript letters are significantly different (P < 0.05)

Fig. 15

Photomicrographs of the rat’s gastric mucosa architecture of different experimental groups stained with hematoxylin and eosin. (a) control group showing the well-preserved normal histological structure of stomach mucosa. (b) ulcerated group showing severe alterations in gastric mucosa with higher power of ulcerative mucosal surface. (c-d) Ulcerated rats treated with ranitidine and Chitosan/PVA hydrogel showed a slight improvement in mucosa structure, confirmed by slight normalization of mucosa. (e) Ulcerated rats treated with chitosan/PVA/ ranitidine hydrogel showed a pronounced recovery in the gastric mucosa

Fig. 16

Photomicrographs of the rat’s gastric mucosa architecture of different experimental groups stained with PAS. (a) control group exhibiting a normal magenta coloring (black arrow) of the gastric mucus glands. (b) ulcerated group showing severe alterations in gastric mucosa with no PAS staining in the mucosa. (c-d) Ulcerated rats treated with ranitidine and free Chitosan/PVA hydrogel showed a slightly intense magenta coloring. (e) Ulcerated rats treated with chitosan/PVA/ ranitidine showed intense uptake of the PAS stain, indicating restoration of the mucosal barrier