title: Increased localized delivery of piroxicam by cationic nanoparticles after intra-articular injection.
abstract: Piroxicam (PRX), a potent nonsteroidal anti-inflammatory drug, is prescribed to relieve postoperative and/or chronic joint pain. However, its oral administration often results in serious gastrointestinal adverse effects including duodenal ulceration. Thus, a novel cationic nanoparticle (NP) was explored to minimize the systemic exposure and increase the retention time of PRX in the joint after intra-articular (IA) injection, by forming micrometer-sized electrostatic clusters with endogenous hyaluronic acid (HA) in the synovial cavity. PRX-loaded NPs consisting of poly(lactic-co-glycolic acid), Eudragit RL, and polyvinyl alcohol were constructed with the following characteristics: particle size of 220 nm, zeta potential of 11.5 mV in phosphate-buffered saline, and loading amount of 4.0% (w/w) of PRX. In optical and hyperspectral observations, the cationic NPs formed more than 50 μm-sized aggregates with HA, which was larger than the intercellular gaps between synoviocytes. In an in vivo pharmacokinetic study in rats, area under the plasma concentration-time curve (AUC0-24 h) and maximum plasma concentration (Cmax) of PRX after IA injection of the cationic NPs were <70% (P<0.05) and 60% (P<0.05), respectively, compared to those obtained from drug solution. Moreover, the drug concentration in joint tissue 24 h after dosing with the cationic NPs was 3.2-fold (P<0.05) and 1.8-fold (P<0.05) higher than that from drug solution and neutrally charged NPs, respectively. Therefore, we recommend the IA cationic NP therapy as an effective alternative to traditional oral therapy with PRX, as it increases drug retention selectively in the joint.
authors.affiliation: Division of Pharmaceutical Sciences, College of Pharmacy, Chung-Ang University, Seoul.
authors.forename: Sung Rae
authors.initials: SR
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Dankook University, Cheonan, Chungnam, South Korea.
authors.forename: Myoung Jin
authors.initials: MJ
authors.lastname: Ho
authors.affiliation: Division of Pharmaceutical Sciences, College of Pharmacy, Chung-Ang University, Seoul.
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Dankook University, Cheonan, Chungnam, South Korea.
authors.forename: Ha Ra
authors.initials: HR
authors.lastname: Cho
authors.affiliation: College of Pharmacy, Dankook University, Cheonan, Chungnam, South Korea.
authors.forename: Han Sol
authors.initials: HS
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Dankook University, Cheonan, Chungnam, South Korea.
authors.forename: Yong Seok
authors.initials: YS
authors.lastname: Choi
authors.affiliation: Division of Pharmaceutical Sciences, College of Pharmacy, Chung-Ang University, Seoul.
authors.forename: Young Wook
authors.initials: YW
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Dankook University, Cheonan, Chungnam, South Korea.
authors.forename: Myung Joo
authors.initials: MJ
authors.lastname: Kang
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D019540:Area Under Curve; D002412:Cations; D004337:Drug Carriers; D004339:Drug Compounding; D006820:Hyaluronic Acid / Q000378:metabolism; D007270:Injections, Intra-Articular; D017746:Joint Capsule / Q000378:metabolism*; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D050997:Nanomedicine; D053758:Nanoparticles; D010894:Piroxicam / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D011142:Polyvinyl Alcohol / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D014018:Tissue Distribution
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002412:Cations; D004337:Drug Carriers; D011108:Polymers; D010894:Piroxicam; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C058665:Eudragit RL; D011142:Polyvinyl Alcohol; D006820:Hyaluronic Acid
keywords: electrostatic interaction; hyaluronic acid; intra-articular injection; local delivery; piroxicam; polymeric nanoparticles