Preparation of drug-containing chitosan gels based on CO2-induced pH switching

The solubilization of poorly water-soluble drugs is a key challenge for ensuring drug effectiveness. One approach is to complex water-soluble polymers with drugs. In this study, we focused on ionic interactions between a polymer and a drug as a novel complexation method. A cationic polymer, chitosan, was used as the polymer, and an anionic drug, indomethacin, was used as the drug. The solubilization of chitosan in water requires acidic conditions. Therefore, we utilized pH switching induced by the introduction of carbon dioxide to adjust the pH in a manner harmless to the human body. This method made it possible to reduce the use of organic solvents harmful to the human body. Using this strategy, a chitosan gel loaded with indomethacin was obtained. Under the preparation conditions of this study, approximately 5.0 mg/mL of indomethacin was dispersed by forming a complex with chitosan. This represents approximately 2000 times greater dispersion compared to its original saturation solubility in water. Furthermore, changing the preparation temperature altered the dispersibility of the loaded drug, and amide bonds were formed between chitosan and indomethacin at higher temperatures, resulting in an uneven gel. As amide bonds have been shown to inhibit drug release, gel formation at an appropriate preparation temperature is necessary to minimize amide bond formation. The dissolution test results showed that the dissolution rate of the drug in the complex increased by approximately 60–200 % compared to that of indomethacin alone. This study demonstrates a new method for solubilizing poorly water-soluble anionic drugs using chitosan. • Polyion complex between a drug and polymer to improve solubility of drugs. • Chitosan used as a carrier for indomethacin, a negatively charged drug. • CO₂ used for pH adjustment to avoid harmful reagents in chitosan treatment. • Improved dispersibility of indomethacin in the chitosan gel. • Drug loading varies with temperature; amide bonds form at higher temperatures.