title: Preparation of polymeric submicron particle-containing microparticles using a 4-fluid nozzle spray drier.
abstract: OBJECTIVE
  We studied a novel method for preparing polymeric submicron particle-containing microparticles using a 4-fluid nozzle spray drier.
  
  
  METHODS
  Ethylcellulose (EC) and poly(lactic-co-glycolic acid) (PLGA), either alone or in combination with polyethylenimine (PEI), were used as polymers to produce submicron particles, and mannitol (MAN) was used as a water-soluble carrier for the microparticles. The polymer and MAN solutions were supplied through different liquid passages of a 4-fluid nozzle and then dried to obtain MAN microparticles containing EC or PLGA submicron particles. The polymer/MAN ratio was controlled by changing the concentration of the polymer and MAN solutions. EC or PLGA microparticles were observed via scanning electron microscopy, and the size of microparticles was determined by image analysis. The particle size distribution of EC or PLGA submicron particles was measured with a super dynamic light scattering spectrophotometer.
  
  
  RESULTS
  The method generated submicron-sized (<1 microm) particles of EC and PLGA. The mean diameters of EC and PLGA particles at a polymer/MAN ratio of 1:10 were 631 and 490 nm, respectively. The mean diameter of PLGA particles decreased as the PLGA/MAN ratio was reduced, reaching approximately 200 nm at a PLGA/MAN ratio of 1:100. The mean diameter of PLGA/PEI particles at PLGA/PEI/MAN ratios of 1:0.5:10 and 1:0.5:100 were 525 and 223 nm, respectively, and their zeta potentials were +50.8 and +58.2 mV, respectively. The size of EC submicron particles could be controlled by varying the spray conditions.
  
  
  CONCLUSIONS
  This study demonstrated that it is possible to prepare polymeric submicron particles dispersed in MAN microparticles in a single process using the 4-fluid nozzle spray drying method. Cationic PLGA particles with a diameter of approximately 200 nm could be prepared by adding PEI, suggesting the possibility of its use as a carrier for delivering DNA into cells. The precipitation of EC may occur by the mutual dispersion and mixing of solvents after collision of EC and MAN mists by antisolvent effect, thereby producing MAN microparticles containing EC submicron particles.
authors.affiliation: Department of Pharmaceutics and Drug Delivery, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan. ozekit@ps.toyaku.ac.jp
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ozeki
authors.forename: Shuji
authors.initials: S
authors.lastname: Beppu
authors.forename: Takuto
authors.initials: T
authors.lastname: Mizoe
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Takashima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yuasa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Okada
mesh_terms: D000336:Aerosols; D002482:Cellulose / Q000031:analogs & derivatives; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004339:Drug Compounding / Q000379:methods*; D005079:Excipients; D019344:Lactic Acid; D008353:Mannitol / Q000737:chemistry; D008855:Microscopy, Electron, Scanning; D049329:Nanostructures; D010316:Particle Size; D011094:Polyethyleneimine / Q000737:chemistry; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers
chemical_list: D000336:Aerosols; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D005079:Excipients; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D008353:Mannitol; C013517:ethyl cellulose; D011094:Polyethyleneimine; D002482:Cellulose