Production of microspheres

A method of producing microspheres comprising a physiologically active substance and a biodegradable polymer, which comprises subjecting a w/o/w emulsion or o/w emulsion wherein said physiologically active substance is in an inner aqueous phase and said biodegradable polymer in an external oil phase to an in-water-drying method under the following conditions:

• 1) the amount of microspheres per m.sup.3 in an external aqueous phase is about 0.1 to about 500 kg,
• 2) the square root of the area (unit:
• m.sup.2) of the liquid surface in contact with the gas phase is about 0.2 to about 4.5 per the cube root of the volume (unit:
• m.sup.3) of the external aqueous phase,
• 3) the w/o/w emulsion or o/w emulsion is replaced at a replacement frequency of about 0.01 to about 10 times/minute,
• 4) a gas is blown toward the w/o/w emulsion or o/w emulsion so that the gas transfer rate near the liquid surface is about 10 to about 200 m/second, and
• 5) the gas is replaced at a replacement frequency of not less than about 0.5 times/minute,
• wherein the physiologically active substance is leuprorelin or leuprorelin acetate, and
• the biodegradable polymer is a lactic acid/glycolic acid polymer having a composition ratio of about 90/10 to 50/50.