Complexation of manidipine with cyclodextrins and their derivatives

Manidipine (MDP, (+/-)-2-[-(diphenylmethyl)-1-piperazinyl]ethylmethyl-1,4-dihydro-2,6-dimethyl-4(m-nitrophenyl)-3,5-pyridinedicarboxylate methyl-ester) is a poorly soluble (<1 mu g/mL) long acting antihypertensive drug. Salt forming with citric or tartaric acid results in a 400 to 600 fold solubility enhancement, respectively, which can be further increased by an order of magnitude with cyclodextrins. Dimethyl-beta CD alone results in a more than 8000 fold solubility enhancement. Besides the strongly enhanced solubility (HNMR)-H-1 spectroscopy also proves the inclusion-type interaction between Manidipine and cyclodextrins. From the attained 5-8 mg/mL solubility of the drug in water an improved bioavailability and pharmacokinetics is expected.