Anhydride prodrugs for nonsteroidal anti-inflammatory drugs.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
This study demonstrates the promise of anhydride prodrugs for extending drug action and shielding the carboxylic acid group.
Shaaya
Osnat
O
Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel 91120.
Magora
Amir
A
Sheskin
Tzviel
T
Kumar
Neeraj
N
Domb
Abraham J
AJ
D000812:Anhydrides / Q000032:analysis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000032:analysis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004487:Edema / Q000188:drug therapy; D005260:Female; D011355:Prodrugs / Q000032:analysis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D000812:Anhydrides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011355:Prodrugs