A wet-milling method for the preparation of cilnidipine nanosuspension with enhanced dissolution and oral bioavailability

Cilnidipine (CLD) is extensively used in the treatment of hypertension; however, it has extremely low solubility which limits its clinical application. The purpose of the present research was to improve the dissolution rate and oral bioavailability of CLD by preparing a nanosuspension. The CLD nanosuspension (CLD-NS) was developed using a wet-milling method with PVP VA64 as the steric stabilizer and SLS as the electrostatic stabilizer. The formulated CLD-NS displayed a narrow and uniform particle size distribution with a mean particle size of 312 nm, and a marked increase in the dissolution of CLD-NS in different dissolution media was observed compared with bulk CLD. The crystallinity of the drug and molecular interactions between drug and stabilizers were investigated by differential scanning calorimetry (DSC), X-ray powder diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR), and Raman spectroscopy, respectively. Furthermore, the in vivo pharmacokinetics of the formulated CLD-NS were evaluated in Sprague-Dawley rats by high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). The results indicated that the C-max and AUC(0-24) of CLD-NS were 3.13-fold and 2.38-fold higher than those of bulk CLD, respectively. Moreover, the C-max and AUC(0-24) of CLD-NS were increased 1.65-fold and 2.17-fold, compared with commercial CLD capsules. These results indicated the significant increase in CLD bioavailability.