Ellagic Acid Inclusion Complex-Loaded Hydrogels as an Efficient Controlled Release System: Design, Fabrication and In Vitro Evaluation

Abstract

Oxidants play a crucial role in the development of oxidative stress, which is linked to disease progression. Ellagic acid is an effective antioxidant with applications in the treatment and prevention of several diseases, since it neutralizes free radicals and reduces oxidative stress. However, it has limited application due to its poor solubility and oral bioavailability. Since ellagic acid is hydrophobic, it is difficult to load it directly into hydrogels for controlled release applications. Therefore, the purpose of this study was to first prepare inclusion complexes of ellagic acid (EA) with hydroxypropyl-β-cyclodextrin and then load them into carbopol-934-grafted-2-acrylamido-2-methyl-1-propane sulfonic acid (CP-g-AMPS) hydrogels for orally controlled drug delivery. Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) were used to validate ellagic acid inclusion complexes and hydrogels. There was slightly higher swelling and drug release at pH 1.2 (42.20% and 92.13%) than at pH 7.4 (31.61% and 77.28%), respectively. Hydrogels had high porosity (88.90%) and biodegradation (9.2% per week in phosphate-buffered saline). Hydrogels were tested for their antioxidant properties in vitro against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). Additionally, the antibacterial activity of hydrogels was demonstrated against Gram-positive bacterial strains (Staphylococcus aureus and Escherichia coli) and Gram-negative bacterial strains (Pseudomonas aeruginosa).

Bioactive Compounds from Plant Origin as Natural Antimicrobial Agents for the Treatment of Wound Infections

“…Another study showed that hydrogels containing EA have antibacterial activity against S. aureus, E. coli, and P. aeruginosa. The growth inhibition zone for S. aureus was 29 mm, while the positive control, consisting of cefepime (1 mg•mL −1 ), reached 32 mm, which proves the great properties of this natural compound [237].…”

“…The confirmed properties of EA to combat P. aeruginosa were provided by Yu et al (2023). The hydrogel products containing EA showed antibacterial properties against Pseudomonas (the growth inhibition zone was 14 mm, while the positive control (cefepime) was 34 mm) [237]. In the Bai et al (2022) study, the EA at 50 µmol prolonged the survival of a model nematode (C. elegans) with P. aeruginosa infection by 79.07% and reduced the number of pathogens in the model organism tissues [245].…”

“…The study by Yu et al (2023) showed the effect of EA (in the form of hydrogel) on E. coli in terms of the limitation of growth capacity (the growth inhibition zone was 31 mm, while for the control group (cefepime), it was 35 mm) [237]. The reports on the 3,3 ′ -di-O-methyl ellagic acid activity (the MIC50 = 0.5 mg•mL −1 , the MBC = 2.5 mg•mL −1 , the MIC value > 2.5 mg•mL −1 ) against E. coli were investigated by Vigbedor et al (2022).…”

Effects of Phenolics on the Physicochemical and Structural Properties of Collagen Hydrogel

“…On the other hand, the swelling ratio of EA cross-linked hydrogels with higher EA concentrations (100% and 200%) was lower than that of pure collagen hydrogel. However, this was due to the significant self-polymerization of EA, which inhibits the extension of collagen fibrils in PBS solution to achieve a reduced swelling ratio [ 33 , 34 ]. However, the swelling ratio was remarkably increased (about 3–15% ( p < 0.05)) with the rise of GA/EA concentrations and time duration during the period from 1 to 50 min and then remained constant from 50 min to 90 min.…”

“…As reported in previous studies [ 49 , 53 ], the increased irregularity of the hydrogel surface can be attributed to enhanced covalent and non-covalent interactions between collagen proteins and phenolic compounds [ 43 ]. The use of GA or EA to cross-link collagen molecules provides additional bonding opportunities, both between collagen molecules and within individual collagen molecules [ 33 ]. As a result, the structural properties of the hydrogel are densified and compacted.…”