To obtain hydroxypropyl methyl cellulose phthalate (HPMCP)/insulin nanospheres by supercritical anti-solvent process, the formation of HPMCP nanoparticles was first investigated. The effects of ratio of the mixed solvent, pressure, temperature, concentration, flow rate of CO2 and solution on forming HPMCP nanoparticles are discussed. It was found that different morphologies of HPMCP could be produced by varying the ratio of DMSO to acetone in the solvent. The operating parameters were optimized for making HPMCP nanoparticles. Formation of HPMCP/insulin nanospheres was further inspected. The nanospheres with the size ranging from 138 nm to 342 nm were obtained. The loading of insulin in the nanospheres ranged from 10.76% to 16.04% and the encapsulation efficiency reached 100%. The release of insulin is also discussed. (C) 2011 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved.