Production of insulin-loaded poly(ethylene glycol)/poly(l-lactide) (PEG/PLA) nanoparticles by gas antisolvent techniques

Insulin and insulin/poly(ethylene glycol) (PEG)-loaded poly(l-lactide) (PLA ) nanoparticles were produced by gas antisolvent (GAS) CO2 precipitation st arting from homogeneous polymer/protein organic solvent solutions. Differen t amounts of PEG 6000 (0, 10, 30, 50, 100, and 200% PEG/PLA w/w) or concent ration of 30%. PEG/PLA with PEGs with different molecular weight (MW; 350, 750, 1900, 6000, 10,000, and 20,000) were used in the preparations. The pro cess resulted in high product yield, extensive organic solvent elimination, and maintenance of > 80% of the insulin hypoglycemic activity. Nanospheres with smooth surface and compact internal structure were observed by scanni ng electron microscopy. The nanospheres presented a mean particle diameter in the range 400-600 nm and narrow distribution profiles. More than 90% of drug and PEG were trapped in the PLA nanoparticles when low MW PEGs were us ed in the formulation, whereas the addition of high MW PEGs significantly r educed the loading yield. In all cases, in vitro release studies showed tha t only a little amount of drug was released from the preparations. However, formulations containing low MW PEGs allowed for a slow but constant drug r elease throughout 1500 h, whereas a burst was obtained by increasing the PE G MW. In conclusion, the GAS process offers a mean to produce protein-loade d nanoparticles possessing the prerequisites for pharmaceutical application s. The PEG added to the formulation was found to play a key role in the sim ultaneous solute precipitation phenomena and in determining the release beh avior and the chemical-physical properties of the formulation. (C) 2001 Wil ey-Liss, Inc. and the American Pharmaceutical Association.