HR1405-01

Combinational utilization of intravenous non-steroidal anti-inflammatory drugs (NSAIDs) with opium analgesic is an effective alternative modality for pain control after surgery. This regimen is known for reducing the risk of addiction induced by opium analgesic. However, current intravenous NSAIDs have solubility problems, limiting their clinical applications. Although loxoprofen exhibits strong anti-inflammatory and analgesic activities with relatively low ulcerogenicity, its relatively low bioavailability makes it not an ideal drug candidate for intravenous injection. We selected the bioactive metabolite (6) of loxoprofen as a candidate and developed a new intravenous NSAID, HR1405-01. This metabolite exhibited significantly stronger anti-inflammatory and analgesic activities than parecoxib sodium injection or ibuprofen injection. The excellent potency and solubility of HR1405-01 allowed the avoidance of utilization of cosolvent in the formulation, resulting in fewer side effects and a better safety profile. Therefore, HR1405-01 might be a promising candidate for the development of a new intravenous NSAID.

Antibody‐mediated extraction followed by chiral high‐performance liquid chromatography (HPLC) was applied to stereoselective determination in human and rat plasma of the active metabolite [(2S,1]R,2[S)‐trans‐alcohol] with three chiral centers of Loxoprofen, a 2‐arylpropionic acid antiinflammatory agent after oral administration. Antiserum against the (1'R,2'S)‐cyclopentanol moiety was obtained from a rabbit immunized with bovine serum albumin conjugate linked to the propionic acid moiety, in which another chiral center is located. Then, the immunoglobulin G purified by a protein A column was coupled to BrCN‐activated Sepharose 4B. Plasma samples were applied to the immobilized antibody column. After washing the column to remove unrequired stereoisomers, a mixture of two diastereomers whose configurations were 1'R,2'S in the cyclopentanol moiety was extracted with 95% methanol. The solvent was evaporated and the residue was derivatized with (+)‐(R)‐1‐(1‐naphthyl)ethylamine as a chiral reagent to separate the diastereomers by HPLC. This combined analytical method showed the stereoselective metabolism of Loxoprofen in human, that is, 64% of the total amount of four trans‐alcohol stereoisomers was in the 2S, 1'R,2'S form, which is the active metabolite. This phenomenon was also observed in rats given Loxoprofen and its (2S)‐ and (2R)‐isomers, and is explained by stereoselective ketone reduction of Loxoprofen to the (1'R,2'S)‐trans‐alcohol and inversion from 2R to 2S in the propionic acid moiety. Antibody‐mediated extraction should be a selective and simple clean‐up method for determining haptens with complicated structures, combined with an appropriate analytical method. © 1992 Wiley‐Liss, Inc.