Effect of partially methylated β cyclodextrin on percutaneous absorption of metopimazine

Abstract

Metopimazine (MPZ) is an antiemetic drug used by oral and rectal administration. A transdermal delivery system of MPZ may present a great advantage for the treatment of nausea and vomiting to improve therapeutic adhesion. MPZ is a lipophilic drug with poor water solubility. Partially methyled β cyclodextrin (PMβ-CD) was tested to enhance percutaneous absorption of MPZ. Complex MPZ/cyclodextrin was characterized by Higushi’s phase solubility, Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) analyses and MPZ octanol partition coefficient was also determinated. The permeation of free MPZ and inclusion complex through pig skin were investigated using Franz’s cells. Four concentrations of cyclodextrins, 0, 5, 10 and 20% were tested. Partition coefficient was depending on pH of the solution. At pH 5.5, MPZ ionization increased the hydrophily (0.71) and at pH 10.3, non-ionized MPZ was the dominant form (591). The solubility of MPZ increased with the concentration of PMβ-CD and the phase solubility diagram is an Ap type. The used characterization analyses demonstrated the formation of an inclusion complex and this complex improved percutaneous absorption of MPZ. No MPZ flux was detected for a suspension of MPZ and it was more important with MPZ hydrochloride, 0.177 ± 0.044 μg/h/cm². Flux was increased to 0.570 ± 0.058 μg/h/cm² with a concentration of 20%. The use of cyclodextrin with MPZ hydrochloride increased also the percutaneous absorption with 0.549 ± 0.175 μg/h/cm² for a concentration of 5%, 0.435 ± 0.031 μg/h/cm² for a concentration of 10% and 0.474 ± 0.054 μg/h/cm² for a concentration of 20%. This study shows that PMβ-CD improves percutaneous penetration of MPZ. But the absorption is not enough to allow a therapeutic effect. Cyclodextrin complex increases MPZ solubility and this bioavailability at the skin surface, and cyclodextrin may also modify the barrier propriety of skin.