COPPER INDOMETHACIN

Warwick, B. The synthesis and purification of copper indomethacin. Ph.D. dissertation. The University of New South Wales, Sydney, Australia, 2001. 

Warwick B, Dehghani F, Foster NR, Biffin JR, Regtop H. Micronization of copper indomethacin using gas antisolvent processes. Ind Eng Chem Res 2002 41(8) 1993-2004. 

Debenedetti and coworkers (88,89) provided one of the first examples of microencapsulation of a drug in the polymeric matrix. Richard and coworkers (90) provided a recent example of the microencapsulation process when they produced microparticles with the encapsulated model protein that showed sustained release. Foster and coworkers (87) also reported precipitation of copper-indomethacin by PVP with a 96-fold enhancement in the dissolution rate of indomethacin. These examples clearly demonstrated the advantages of using supercritical fluid processing for the preparation of polymer-drug formulations with potentially improved therapeutic properties. 

Industrial and Engineering Chemistry Research 43, No.4, 18th Feb.2004, p. 1103-12 INCREASING COPPER INDOMETHACIN SOLUBILITY BY COPRECIPITATION WITH POLY(VINYLPYRROLIDONE) USING THE AEROSOL SOLVENT EXTRACTION SYSTEM Meure LA Warwick B Dehghani F Regtop H L Foster N R... 

Indomethacin Griseofulvin Hydrocortisone Sodium chloride Copper... 

The list of compounds presented in Table 6.4 includes copper complexes of well-known antiarthritic drugs, including salicylic acid, aspirin, diflunisal, niflumic acid, D-penicillamine, hydrocortisone, dexamethasone, dimethyl-sul-phoxide, clopirac, ketoprofen, ibuprofen, (+ )-naproxen, indomethacin, me-fenamic acid, thiomalic acid, phenylbutazone, lonazolac, isoxicam and azo-propazone. While there has been much discussion concerning the qualitative and quantitative activities of these complexes [136, 152-156, 164, 187], it is... 

More recent studies have clearly shown that Cu(II)(anthranilate)2, Cu(II)(salicylate)2, Cu(II)2(3,5-DIPS)4, Cu(II)2(aspirinate)4, Cu(II)2(niflu-mate)4, and Cu(II)2(indomethacin)4 are more effective analgesics than their parent ligands [93]. As shown in Table 6.5, copper complexes of salicylic acid,... 

DIPS, aspirin, niflumic acid and indomethacin were more effective than their parent compounds and CUCI2 or Cu2(acetate)4 in writhing and polyarth-ritic pain models. In addition, the copper complex of indomethacin was found to be as effective as morphine in both pain models and the amount of copper... 

Copper(II)(salicylate)2 was also shown to be more effective than cimetidine in preventing ulcers induced by aspirin, indomethacin or cold-stress Table 6.21) [263],... 

Copper chelates have also been found to inhibit superoxide-induced lipid peroxidation in other in vitro systems, Copper(II)2(aspirinate)4, Cu(I)/(II)-penicillamine, and Cu(II)2(indomethacin)4 were as effective as or more effective than Cu-Zn SOD in inhibiting erythrocyte membrane and liver microsomal membrane peroxidation [636]. Copper(II)(tyrosinate)2 was also found to be a very efficient inhibitor of NADPH-dependent lipid peroxidation in phe-nobarbital-induced rat liver microsomes [698]. Even though Cu-Zn SOD was ineffective in inhibiting this peroxidation, it was suggested that superoxide and other radicals participated in this NADPH-dependent peroxidation of microsomal unsaturated fatty acids and that these radicals react in domains of the microsomal membrane that are inaccessible to Cu-Zn SOD. The small size and lipophilic character of Cu(II)(tyrosinate)2 allow penetration into these domains and the prevention of peroxidation. 

The antiinflammatory drugs indomethacine (l-(p-chlorobenzoyl)-5-methoxy-2-methyl-indole acetate) and lonazolac (3-p-chlorophenyl)-l-phenyl-pyrazole-4-acetate) form thermodynamically stable copper complexes in aprotic solutions, which are highly superoxide dismutase active An example for the structure of these... 

Surprisingly, in such complexes, the copper-copper distance (263 pm) is very close to that of metallic copper A spin-spin interaction, namely an antiferromagnetic coupling of the copper is observed. Two coordination sites in the copper-copper axis can be readily replaced by superoxide. For Cu2(indomethacin)4 a second-order rate... 

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