title: Monitoring release of ketoprofen enantiomers from biodegradable poly(D,L-lactide-co-glycolide) injectable implants.
abstract: A stereoselective reversed-phase HPLC assay was developed that could simultaneously quantify S-(+) and R-(-) enantiomers of ketoprofen in release samples. Racemic ketoprofen (rac-KET) and its S-(+) enantiomer (S-(+)-KET) were dissolved in an injectable viscous polymer solution consisting of the biodegradable poly(D,L-lactide-co-glycolide, 70:30) (D,L-PLG) and a solvent, N-methyl-2-pyrrolidone (NMP). Once injected into an aqueous environment, the polymeric mixture solidified into a solid implant due to the leaching of NMP. In vitro release studies show that such implants with ketoprofen can provide sustained release of the drug lasting about three months in a pH 7.4 release medium. Moreover, a preferential faster S-(+)-KET release over R-(-)-KET was observed for the implants containing 4%, 7%, and 10% of racemic ketoprofen in the neutral pH 7.4 release medium. Stereoselective release was minimal in the first 42 days in vitro but became very pronounced at later time points. When S-(+)-KET was incorporated into the polymeric mixture, its release was also faster than that of the racemic ketoprofen, confirming the stereoselective release of ketoprofen from the d,l-PLG implants. The observed stereoselective release of KET at pH 7.4 was most likely produced by chiral interactions between KET enantiomers and transiently produced D-lactic acid or L-lactic acid rich domains within the implants during D,L-PLG degradation. However, such stereoselective release was not observed in pH 10.0 release medium, probably due to a much faster and homogeneous polymer degradation. The study suggests possible stereoselective release of racemic drugs from D,L-PLG microspheres and implants in vivo.
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, 310031, Hangzhou, Zhejiang, People's Republic of China.
authors.forename: S H
authors.initials: SH
authors.lastname: Wang
authors.forename: Z H
authors.initials: ZH
authors.lastname: Liang
authors.forename: S
authors.initials: S
authors.lastname: Zeng
mesh_terms: D020341:Absorbable Implants; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000032:analysis / Q000737:chemistry*; D002021:Buffers; D002138:Calibration; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid / Q000379:methods* / Q000592:standards; D004339:Drug Compounding; D004343:Drug Implants; D006863:Hydrogen-Ion Concentration; D007267:Injections; D007660:Ketoprofen / Q000032:analysis / Q000737:chemistry*; D019344:Lactic Acid / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D011760:Pyrrolidinones / Q000737:chemistry; D015203:Reproducibility of Results; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013237:Stereoisomerism; D013997:Time Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002021:Buffers; D004343:Drug Implants; D011108:Polymers; D011760:Pyrrolidinones; D012997:Solvents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D007660:Ketoprofen; C038678:N-methylpyrrolidone