POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF KETOPROFEN AND RELATED COMPOUNDS WITH VERY FAST SKIN PENETRATION RATE

摘要

The novel positively charged pro-drugs of ketoprofen and fenoprofen in the general formula(1) 'Structure 1' were designed and synthesized. The compounds of the general formula(1) 'Structure 1' indicated above can be prepared from functional derivatives of ketoprofen and fenoprofen, (for example acid halides or mixed anhydrides), by reaction with suitable alcohols, thiols, or amines. The positively charged amino groups of these pro-drugs not only largely increases the solubility of the drugs, but also bonds to the negative charge on the phosphate head group of membranes and pushes the pro-drug into the cytosol. The results suggest that the pro-drugs, diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH diffuses through human skin ~125 times faster than does ketoprofen and fenoprofen. It takes 1-2 hours for ketoprofen or fenoprofen to reach the peak ketoprofen or fenoprofen plasma level when they are taken orally, but diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH or diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH only took about 40 minutes to reach the ketoprofen or fenoprofen peak plasma level. In plasma, more than 90% of these pro-drugs can change back to the drug in a few minutes. The prodrugs can be used medicinally in treating any ketoprofen and fenoprofen-treatable conditions in humans or animals. The prodrugs can be administered not only orally, but also transdermally for any kind of medical treatments and avoid most of the side effects of ketoprofen and fenoprofen, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enables ketoprofen and fenoprofen to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of ketoprofen and fenoprofen. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.