New carrier for specific delivery of drugs to the brain.
1,4-Dihydropyridines were thoroughly investigated as carriers for specific drug delivery to the brain and were found very efficient. The main problem which arises in their application in pharmaceutical preparations, is the short shelf-life time due to hydration and/or oxidation. To overcome these problems, a new carrier system is suggested. Many of 1,4-dihydropyridine-3,5-dicarboxylate derivatives are used as calcium channel blockers which are known to have long shelf-life time, and at the same time, they are safe, with no reported neurotoxicity. Since efficiency of brain specific delivery depends on the rate of oxidation of the dihydropyridine carrier, (the faster the rate, the higher the efficiency), these 3,5-dicarbonyl compounds have almost of no brain-specific delivery properties. N-alkoxycarbonylmethyl derivatives of 1,4-dihydropyridine-3,5-dicarboxylate, a new carrier system is suggested and expected to be stable enough for formulation and storage. The drug moiety will be connected to the 3,5-dicarbonyl groups in the form of esters or amides. The suggested drug-carrier once delivered and distributed in the body, will be subjected to several sequential enzymatic hydrolytic and oxidative processes. The D-carrier is designed so that, the rate of hydrolysis of the ester group at the nitrogen atom should be faster than that of the hydrolysis and release of the drug moiety. The stability and efficiency of brain specific delivery of model drugs were investigated. The in vitro and in vivo studies proved the efficiency of brain specific delivery of the carrier and at the same time its shelf life stability. The results suggest that the designed carrier is promising to be used in application of pharmaceutical formulation.
Sheha
Mahmoud
M
Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University, Assuit 71526, Egypt. sheha@accaun.eun.eg
Al-Tayeb
Ali
A
El-Sherief
Hosny
H
Farag
Hassan
H
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D004095:Dihydropyridines / Q000737:chemistry* / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000737:chemistry* / Q000493:pharmacokinetics*; D015195:Drug Design; D004355:Drug Stability; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D010084:Oxidation-Reduction; D010627:Phenethylamines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D011817:Rabbits; D014018:Tissue Distribution; D014363:Tryptamines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics
D004095:Dihydropyridines; D004337:Drug Carriers; D010627:Phenethylamines; D014363:Tryptamines; C038806:1,4-dihydropyridine