Microsphere system have been used drug delivery systems for a variety of drugs. Microsphere systems, however, may release the drug quickly during the first day. The initial burst of drug release may results in lower therapeutic efficiency and cause side effects. We hypothesized that microsphere/hydrogel combination systems can refrain the initial burst of drug release. To test this hypothesis, we prepared the microspheres using a monoaxial one-nozzle ultrasonic atomizer with an encapsulation efficiency of about 80% and microsphere particle size of about 57 µm. Microsphere/hydrogel combination formulation were prepared by mixing drug-loaded microspheres and Pluronic (PH) and crosslinked hyaluronic acid (HA). All formulations were manufactured as solution forms and changed to gel when injected into the subcutaneous of Sprague-Dawley (SD) rats. While confirming that the persistence of injectable materials in vivo, we confirmed that the initial burst of drug release was suppressed by in situ forming hydrogels. The maintenance period of the in situ forming hydrogel is a very important factor in drug release period. We conclude that the properties of hydrogels affect the inhibition of initial release of drug and sustained drug release. In conclusion, we believe that the current research is an effective drug delivery system and that will be useful drug delivery system in the future.