Design of Highly Dispersible PLGA Microparticles in Aqueous Fluid for the Development of Long-Acting Release Injectables

Chem Pharm Bull (Tokyo). 2017;65(2):157-165. doi: 10.1248/cpb.c16-00746.

Abstract

In this study, we developed highly dispersible polylactic glycolic acid (PLGA) copolymer microparticles (MRPs) in aqueous fluid. A solution containing both dissolved aripiprazole as a model drug and PLGA were spray-dried to make MRPs. The resultant MRPs were further co-processed with water-soluble additives and a surfactant to improve their dispersion behavior. The granules containing MRPs and additives, termed granulated microparticles (G-MRPs) were prepared by a newly established drop freeze-drying technique. The physicochemical properties of MRPs and G-MRPs were evaluated as a long-acting release depot injectable. The MRPs were spherical particles with diameters of approximately 1 to 20 µm and strongly assembled to one another in the aqueous phase, forming large aggregations. In contrast, the G-MRPs were spherical granules with diameters of approximately 200 to 400 µm that displayed a microparticles-in-granule structure in which small MRPs were embedded in the porous matrix inside the granules. When the G-MRPs were placed in water, the porous matrix base was immediately dissolved, and each embedded MRP was individually released, thus inducing monodispersion and significantly improved dispersibility. The excellent dispersibility was attributed to the water-soluble porous network structure mainly composed of D-mannitol and the steric hindrance effects derived from the polymeric molecular chains. These properties may give rise to the excellent passage of PLGA microparticles through needles for use in depot formulation suspensions. A crystalline evaluation of the G-MRPs suggested that the drug and PLGA molecularly interacted and that their thermodynamic stability was improved.

MeSH terms

  • Aripiprazole / chemistry
  • Delayed-Action Preparations*
  • Drug Carriers / chemistry*
  • Freeze Drying
  • Injections / methods*
  • Lactic Acid / chemistry*
  • Microspheres*
  • Particle Size
  • Polyglycolic Acid / chemistry*
  • Polylactic Acid-Polyglycolic Acid Copolymer

Substances

  • Delayed-Action Preparations
  • Drug Carriers
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Lactic Acid
  • Aripiprazole