Injectable Sustained-Release Depots of PLGA Microspheres for Insoluble Drugs Prepared by hot-Melt Extrusion.

PURPOSE: Progesterone (PRG) was selected as a model drug to develop a long-acting injection system for poorly water-soluble drugs.

METHODS: Microspheres with high density-low porosity were prepared by hot-melt extrusion (HME) combined with wet-milling as the representative formulation, and a microcrystal suspension was also studied as a comparison. The morphology, particle size and distribution, polymorphism, drug distribution, density and porosity were characterized by scanning electron microscopy, laser diffraction particle size analyzer, power X-ray diffraction and DSC respectively. The in vivo performance of the different formulations within 7 days after intramuscular injection was evaluated in male SD rats.

RESULTS: The drug-loading rate of the microspheres could be as high as 40%. The average initial burst release of the microspheres (PLGA lactide:glycolide = 75:25) was only 6.7% much lower than that of the microsuspension (25.7%) and a sustained release was exhibited for at least 7 days. The release mechanism was speculated to be as follows. The microspheres are a drug depot with drug microcrystals in the PLGA matrix which is a layer by layer honeycomb structure.

CONCLUSIONS: Microspheres prepared by HME combined with wet-milling could achieve a long-term sustained release effect as a novel long-acting formulation strategy.