A type of multi-unit floating alginate (Alg) microspheres was prepared by the ionotropic gelation method with calcium carbonate (CaCO3) being used as gas-forming agent. Attempts were made to enhance the drug encapsulation efficiency and delay the drug release by adding chitosan (Cs) into the gelation medium and by coating with Eudragit, respectively. The gastrointestinal transit of optimized floating sustained-release microspheres was compared with that of the non-floating system manufactured from identical material using the technique of gamma-scintigraphy in healthy human volunteers. It was found that the drug encapsulation efficiency of Cs–Alg microspheres was much higher than that of the Ca–Alg microspheres, and coating the microspheres with Eudragit RS could extend the drug release significantly. Both uncoating and coating microspheres were able to continuously float over the simulated gastric fluid (SGF) for 24 h in vitro. Prolonged gastricretention time (GRT) of over 5 h was achieved in the volunteer for the optimized coating floating microspheres (FM). In contrast, non-floating system (NFM) could be emptied within 2.5 h. In the present study, a multi-unit system with excellent floating ability, optimum drug entrapment efficiency and suitable drug release pattern has been developed.