Abstract: A novel mucoadhesive microcapsule with drug-resin complex core loaded with berberine hydrochloride (BH) was developed and optimized. Drug-ion exchange resin (IER) complex was prepared by static method which stirring IER in drug solution at certain conditions. The influences of different IERs, different temperature, pH values and concentrations of drug solution on the drug loading were investigated. IER complex was coated by emulsion-solvent evaporation method. The coating fluid formulation was optimized using central composite design-response surface methodology, where the ratio between Carbopol 934 and IER (X₁), the ratio between Eudragit and IER (X₂) and the ratio between Eudragit RL and RS (X₃) were taken as independent variables. Time of cumulative release 85% (Y₁) and percentage of gastric retention (Y₂) were taken as response variables. Drug loading achieved a high level and more drug available in the condition of IER (IRP 88), 37 ℃, pH 5 and 1.0 mg·mL^-1 drug solution. When X₁=0.75, X₂=0.9, X₃=0.6, the time of cumulative release reached 85% at 300 min, the highest percentage of gastric retention in the range of this experiment were procured.