Positively charged water-soluble prodrugs of ibuprofen with very fast skin penetration rate

Abstract

The novel positively charged pro-drugs of ibuprofen in the general formula (I) ''Structure 1'' were designed and synthesized. The compounds of the general formula (I) ''Structure 1'' indicated above can be prepared from functional derivatives of ibuprofen, (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 experiment results suggest that the pro-drug, diethylaminoethyl 2-(p-isobutylphenyl) propionate.AcOH, diffuses through human skin -250 times faster than ibuprofen itself and -125 times faster than ethyl 2-(p-isobutylphenyl) propionate. 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 ibuprofen-treatable conditions in humans or animals and be administered not only orally, but also transdermally for any kind of medical treatments and avoid most of the side effects of ibuprofen, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enable the ibuprofen to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of ibuprofen.

Description

technical field

[0001] The present invention relates to positively charged water-soluble prodrugs of 2-(p-isobutylphenyl)propionic acid (ibuprofen) and their medical use in the treatment of any ibuprofen-treatable condition in humans or animals . Specifically, the present invention is to overcome the side effects brought by the use of ibuprofen. These prodrugs can be administered orally or transdermally. technical background

[0002] Ibuprofen is a propionate NSAID. Ibuprofen was synthesized for the first time in 1964 (J.S.Nicholson and S.S.Adams, Br.Patent No.971,700) and was first used as a medicine in Europe. Ibuprofen was more effective than aspirin in anti-inflammatory and inhibition of prostaglandin biosynthesis experiments. "PDR Generics" (PDR Generics, 1996, second edition, Medical Economics, Montvale, New Jersey, pg 243) lists the various medical uses of ibuprofen. Ibuprofen can be used to relieve the symptoms of rheumatoid arthritis and osteoarthritis, reduce ...

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