title: Preparation and characterization of a nanoparticulate formulation composed of PEG-PLA and PLA as anti-inflammatory agents.
abstract: We have prepared polymeric nanoparticles using a blend of poly(lactic acid) and monomethoxy-polyethyleneglycol(PEG)-polylactide block copolymer along with betamethasone disodium phosphate (BP). Nanoparticles have been screened for anti-inflammatory activity using experimental rat models of inflammation. In the present study, we examined the degradation of nanoparticles in vitro during incubation. We found that the nanoparticles lost the PEG chains present on their surfaces within a few days, and subsequently gradually released BP. Furthermore, we found that these nanoparticles preferentially accumulated in the inflammatory lesion in adjuvant arthritis rat models, and that the amount of BP gradually depleted from the lesion over 14 days. These results suggested the mechanism underlying the anti-inflammatory effect of the nanoparticles in vivo: the initial accumulation of BP in the lesion due to the enhanced permeability and retention effect, the subsequent internalization in inflammatory macrophages due to the loss of PEG, and the release of BP in cells during the hydrolysis of polymers. The nanoparticles were successfully prepared on a large-scale and stably stored in the form of a freeze-dried formulation for at least 69 weeks below 25 degrees C. These results suggest that the nanoparticles can be used as an anti-inflammatory pharmaceutical formulation in a clinical setting.
authors.affiliation: Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan. tishihar@kumamoto-u.ac.jp
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ishihara
authors.forename: Miyuki
authors.initials: M
authors.lastname: Takahashi
authors.forename: Megumu
authors.initials: M
authors.lastname: Higaki
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Mizushima
authors.forename: Tohru
authors.initials: T
authors.lastname: Mizushima
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D001623:Betamethasone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004355:Drug Stability; D004356:Drug Storage; D005612:Freeze Drying; D005620:Freund's Adjuvant; D006868:Hydrolysis; D007773:Lactates / Q000737:chemistry*; D008297:Male; D009161:Mycobacterium; D053758:Nanoparticles; D036103:Nanotechnology; D010539:Permeability; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D011917:Rats, Inbred Lew; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D013696:Temperature; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D007773:Lactates; C088513:poly(lactic acid-ethylene glycol); D011092:Polyethylene Glycols; C028994:betamethasone sodium phosphate; D005620:Freund's Adjuvant; D001623:Betamethasone