Effect of Citric Acid as Cross-linking Agent on Insulin Loaded Chitosan Microspheres

Chitosan microspheres have been prepared for insulin controlled release delivery. After preparation of insulin chitosan microspheres by emulsification-cross linking process, the effects of chitosan quantity (200-400 mg) and citric acid concentration as a cross-linking agent (70-140 mg) were studied on the morphology, particle size, loading efficiency, flow and release of insulin from the microspheres. Mean particle size was 35-44 urn, insulin loading and preparation efficiency of microspheres were between 4.7-6.8% w/w and 70%, respectively. In microspheres containing citric acid, drug release followed the Higuchi model while in its absence a non-Fickian mechanism was dominant. Citric acid had no effect on stability, particle size, production efficiency and flow of the microspheres while decreased the loading efficiency. Increasing the chitosan content, increased particle size and release parameters like T50% (time required to release 50% of drug) and MDT (mean dissolution time). The increase of citric acid, increased DEB% (dissolution efficiency up to 8 h) of insulin but decreased the T50% and MDT. The results showed that not only citric acid does not cause reduction of release rate of insulin from chitosan microspheres but in fact accelerates the release rate.