Enhancing Mucoadhesive Properties of Gelatin through Chemical Modification with Unsaturated Anhydrides

Abstract

Gelatin is a water-soluble natural polyampholyte with poor mucoadhesive properties. It has traditionally been used as a major ingredient in many pharmaceuticals, including soft and hard capsules, suppositories, tissue engineering, and regenerative medicine. The mucoadhesive properties of gelatin can be improved by modifying it through conjugation with specific adhesive unsaturated groups. In this study, gelatin was modified by reacting with crotonic, itaconic, and methacrylic anhydrides in varying molar ratios to yield crotonoylated-, itaconoylated-, and methacryloylated gelatins (abbreviated as Gel-CA, Gel-IA, and Gel-MA, respectively). The successful synthesis was confirmed using 1 H NMR, FTIR spectroscopies, and colorimetric TNBSA assay. The effect of chemical modification on the isoelectric point was studied through viscosity and electrophoretic mobility measurements. The evolution of the storage (G′) and loss (G′′) moduli was employed to determine thermoreversible gelation points of modified and unmodified gelatins. The safety of modified gelatin derivatives was assessed with an in vivo slug mucosal irritation test (SMIT) and an in vitro MTT assay utilizing human pulmonary fibroblasts cell line. Two different model dosage forms, such as physical gels and spray-dried microparticles, were prepared and their mucoadhesive properties were evaluated using a flow-through technique with fluorescent detection and a tensile test with ex vivo porcine vaginal tissues and sheep nasal mucosa. Gelatins modified with unsaturated groups exhibited superior mucoadhesive properties compared to native gelatin. The enhanced ability of gelatin modified with these unsaturated functional groups is due to the formation of covalent bonds with cysteine-rich subdomains present in the mucin via thiol−ene click Michael-type addition reactions occurring under physiologically relevant conditions.

Exploring Mucoadhesive and Toxicological Characteristics Following Modification of Linear Polyethylenimine with Various Anhydrides

“…In an NMR spectroscopic study, they reported the disappearance of vinyl protons of polyethylene glycol diacrylate when mixed with mucin . Subsequently, our research group demonstrated a similar enhancement in the mucoadhesive properties of cationic, anionic, and neutral polymers upon the introduction of methacryloyl moieties . In our most recent study, − we further showed that the mucoadhesive properties of gelatin could be significantly enhanced by modifying this biopolymer through reactions with crotonic, itaconic, and methacrylic anhydrides.…”

“…The strong adhesion of FITC-methacrylated L-PEI and crotonylated L-PEI can be attributed to the presence of unsaturated CC within these polymers, which could potentially form covalent bonds with thiol groups present on mucosal surfaces . The contribution of the amine groups within these polymers to adhesion will be minimal at pH to 7.4, since their macromolecules will be either noncharged or negatively charged.…”

Multifunctional Self-Healing Carbon Dot–Gelatin Bioadhesive: Improved Tissue Adhesion with Simultaneous Drug Delivery, Optical Tracking, and Photoactivated Sterilization

“…The well-suited backbone of gelatin offers superb biocompatibility, biodegradability, and natural abundance that comes at meagre price. , Despite these advantages, gelatin lacks cohesion and interfacial adhesion strength, which could be tuned through modifications of surface functionalities . Physical mixing with tannic acid/PEG, photo-cross-linking with thiol/acrylate, − cryo-polymerization, and reaction with transglutaminase are reportedly used to enhance adhesion and cohesion of gelatin. Chemical cross-linking with formaldehyde and glutaraldehyde in resorcinol has been found to enhance the bonding strength of gelatin-resorcin-formalin (GRF) and gelatin-resorcin-glutaraldehyde glues. , However, toxicological implications arise from the release of the aldehydes upon degradation of the bioadhesive.…”