Ketorolak-dekstran konjugati: sinteza, in vitro i in vivo vrednovanje

Abstract

Ketorolac is a non-steroidal anti-inflammatory drug. Dextran conjugates of ketorolac (KD) were synthesized and characterized to improve ketorolac aqueous solubility and reduce gastrointestinal side effects. An N-acylimidazole derivative of ketorolac (KAI) was condensed with a model carrier polymer, dextran of different molecular masses (40000, 60000, 110000 and 200000). IR spectral data confirmed formation of ester bonding. Ketorolac contents were evaluated by UV-spectrophotometric analysis. The molecular mass was determined by measuring viscosity using the Mark-Howink-Sakurada equation. In vitro hydrolysis studies were performed in aqueous buffers (pH 1.2, 7.4, 9) and in 80% (V/V) human plasma (pH 7.4). At pH 9, a higher rate of ketorolac release from KD was observed as compared to aqueous buffer of pH 7.4 and 80% human plasma (pH 7.4), following first-order kinetics. In vivo biological screening in mice and rats indicated that conjugates retained analgesic and anti-inflammatory activities with significantly reduced ulcerogenicity compared to the parent drug.U radu je opisana sinteza konjugata dektrana i protuupalnog lijeka ketorolaka (KD). Konjugati su pripravljeni da bi se povećala topljivost ketorolaka u vodi i smanjila njegova nusdjelovanja u gastrointestinanom traktu. Ketorak je prvo preveden u N-acilimidazolni derivat (KAI) koji je kondenziran s polimernim nosačem, dekstranom različitih molekulskih masa (40000, 60000, 110000 i 200000). IR-spektri potvrdili su nastajanje esterske veze. Udio ketorolaka u konjugatu određen je UV-spektrofotometrijskom analizom. Molekulske mase određene su mjerenjem viskoznosti koristeći Mark-Howink-Sakurada jednadžbu. Hidroliza in vitro praćena je u puferskim otopinama (pH 1,2, 7,4 i 9) i u 80% V/V humanoj plazmi (pH 7,4). Pri pH 9 primjećeno je značajno brže oslobađanje ketorolaka iz KD nego u puferskoj otopini pH 7,4 i krvnoj plazmi. Oslobađanje je prati kinetiku prvog reda. In vivo biološka ispitivanja na miševima i štakorima ukazuju da konjugati imaju analgetsko i protuupalno djelovanje, a značajno smanjeno ulcerogeno djelovanje