Anhydride prodrugs for nonsteroidal anti-inflammatory drugs

• Published in: Pharmaceutical research 2003-02, Vol.20 (2), p.205-211
• Main Authors: SHAAYA, Osnat, MAGORA, Amir, SHESKIN, Tzviel, KUMAR, Neeraj, DOMB, Abraham J
• Format: Article
• Language: English
• Subjects: Analgesics; Anhydrides - analysis; Anhydrides - chemistry; Anhydrides - pharmacokinetics; Animals; Anti-inflammatory agents; Anti-Inflammatory Agents, Non-Steroidal - analysis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Bioavailability; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Chromatography; Edema - drug therapy; Fatty acids; Female; Medical sciences; Nonsteroidal anti-inflammatory drugs; Pharmacology. Drug treatments; Prodrugs - analysis; Prodrugs - chemistry; Prodrugs - pharmacokinetics; Rats; Rats, Sprague-Dawley; Spectrum analysis
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1022214919481

The objective of this study was to synthesize anhydride prodrugs for prolong action to shield the carboxylic acid group from irritative effects and to temporary hydrophobize the drug so that it becomes accessible to aqueous media when the anhydride residue is hydrolyzed. Ibuprofen, a nonsteroidal anti-inflammatory agent, was used as a representative drug for anhydride derivatization. Mixed anhydrides of ibuprofen with fatty acids of different chain length were prepared by reacting acid chloride derivatives with the corresponding acid in the presence of acid acceptor and two-phase reaction. Mixed anhydrides were also prepared by dehydration reaction using acetic anhydride and anhydride interchange of symmetric anhydrides. The analgesic effects of mixed anhydride prodrugs were tested using nonsteroidal anti-inflammatory drug rat paw edema model. In vitro degradation of mixed anhydrides and drug release were monitored by high-performance liquid chromatography. Ibuprofen was bound to aliphatic and aromatic acids via an anhydride bond in high reaction yields (>85%) with high mixed anhydride content (>80%). The mix anhydride was purified by chromatography and stored at 4 degrees C to minimize conversion into the symmetric anhydride. These anhydride derivatives hydrolyzed at different time intervals depending on the hydrophobicity of conjugated acid. In vivo testing of the ibuprofen anhydride derivatives for analgesic effect indicated an extended action of the drug for over 24 h as a function of the fatty acid chain length. This study demonstrates the promise of anhydride prodrugs for extending drug action and shielding the carboxylic acid group.