Improved delivery through biological membranes. 11. A redox chemical drug-delivery system and its use for brain-specific delivery of phenylethylamine.

A dihydropyridine in equilibrium pyridinium salt type redox system is described as a general and flexible method for site-specific and sustained delivery of drugs to the brain. According to this, a biologically active compound linked to a lipoidal dihydropyridine carrier easily penetrates the blood-brain barrier. Oxidation of the carrier part in vivo to the ionic pyridinium salt prevents its elimination from the brain, while elimination from the general circulation is accelerated. Subsequent cleavage of the quaternary carrier-drug species results in sustained delivery of the drug in the brain and facile elimination of the carrier part. The concept is illustrated with phenethylamine as the drug and trigonelline as the quaternary carrier. One injection to rats of 1-methyl-3-(N-phenethylcarbamoyl)-1,4-dihydropyridine resulted in continuous build up in the brain of the corresponding 1-methyl-3-(N-phenethylcarbamoyl)pyridinium salt, reaching a maximum at about 80 min. At this time, the general circulation was practically void of either compound, while the accumulated carrier-drug species provided a source for sustained drug delivery only in the brain.