title: An experimental design approach to the preparation of pegylated polylactide-co-glicolide gentamicin loaded microparticles for local antibiotic delivery.
abstract: The present paper takes into account the DOE application to the preparation process of biodegradable microspheres for osteomyelitis local therapy. With this goal gentamicin loaded polylactide-co-glycolide-copolyethyleneglycol (PLGA-PEG) microspheres were prepared and investigated. Two preparation protocols (o/w and w/o/w) with different process conditions, and three PLGA-PEG block copolymers with different compositions of lactic and glycolic acids and PEG, were tested. A Design Of Experiment (DOE) screening design was applied as an approach to scale up manufacturing step. The results of DOE screening design confirmed that w/o/w technique, the presence of salt and the 15%w/v polymer concentration positively affected the EE% (72.1-97.5%), and span values of particle size distribution (1.03-1.23), while salt addition alone negatively affected the yield process. Process scale up resulted in a decrease of gentamicin EE% that can be attributed to the high volume of water used to remove PVA and NaCl residues. The results of in vitro gentamicin release study show prolonged gentamicin release up to three months from the microspheres prepared with salt addition in the dispersing phase; the behavior being consistent with their highly compact structure highlighted by scanning electron microscopy analysis. The prolonged release of gentamicin is maintained even after embedding the biodegradable microspheres into a thermosetting composite gel made of chitosan and acellular bovine bone matrix (Orthoss® granules), and the microbiologic evaluation demonstrated the efficacy of the gentamicin loaded microspheres on Escherichia coli. The collected results confirm the feasibility of the scale up of microsphere manufacturing process and the high potential of the microparticulate drug delivery system to be used for the local antibiotic delivery to bone.
authors.affiliation: Department of Drug Sciences, Viale Taramelli 12, University of Pavia, 27100, Pavia, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Dorati
authors.affiliation: Department of Drug Sciences, Viale Taramelli 12, University of Pavia, 27100, Pavia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: DeTrizio
authors.affiliation: Department of Drug Sciences, Viale Taramelli 12, University of Pavia, 27100, Pavia, Italy.
authors.forename: Ida
authors.initials: I
authors.lastname: Genta
authors.affiliation: Department of Drug Sciences, Viale Taramelli 12, University of Pavia, 27100, Pavia, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Grisoli
authors.affiliation: Department of Drug Sciences, Viale Taramelli 12, University of Pavia, 27100, Pavia, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Merelli
authors.affiliation: IENI CNR Lecco Unit, Via Promessi Sposi 29, 23900, Lecco, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Tomasi
authors.affiliation: Department of Drug Sciences, Viale Taramelli 12, University of Pavia, 27100, Pavia, Italy. Electronic address: bice.conti@unipv.it.
authors.forename: Bice
authors.initials: B
authors.lastname: Conti
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D048271:Chitosan / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D065546:Drug Liberation; D004926:Escherichia coli / Q000187:drug effects; D005839:Gentamicins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D011098:Polyglactin 910 / Q000737:chemistry*; D012107:Research Design; D013818:Thermogravimetry
chemical_list: D000900:Anti-Bacterial Agents; D004337:Drug Carriers; D005839:Gentamicins; C102418:poly(lactic-glycolic acid)-poly(ethyleneglycol) copolymer; D011098:Polyglactin 910; D011092:Polyethylene Glycols; D048271:Chitosan
keywords: Bone delivery; DOE; Gentamicin; Microspheres; Osteomyelitis; Polyethyleneglycol; Polylactide-co-glycolide