Enhancement of oral bioavailability of cilostazol by forming its inclusion complexes

Abstract

The study was designed to investigate the effect of cyclodextrins (CDs) on the solubility, dissolution rate, and bioavailability of cilostazol by forming inclusion complexes. Natural CDs like beta-CD, gamma-CD, and the hydrophilic beta-CD derivatives, DM-beta-CD and HP-beta-CD, were used to prepare inclusion complexes with cilostazol. Phase solubility study was carried out and the stability constants were calculated assuming a 1:1 stoichiometry. Solid cilostazol complexes were prepared by coprecipitation and kneading methods and compared with physical mixtures of cilostazol and cyclodextrins. Prepared inclusion complexes were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction (XRD) studies. In vitro dissolution study was performed using phosphate buffer pH 6.4, distilled water, and HCl buffer pH 1.2 as dissolution medium. The optimized inclusion complex was studied for its bioavailability in rabbit and the results were compared with those of pure cilostazol and Pletoz-50. Phase solubility study showed dramatic improvement in the solubility of drug by formation of complexes, which was further increased by pH adjustment. The dissolution rate of cilostazol was markedly augmented by the complexation with DM-beta-CD. DSC and XRD curves showed sharp endothermic peaks indicating the reduction in the microcrystallinity of cilostazol. Selected inclusion complex was also stable at ambient temperature up to 6 months. The in vivo study revealed that DM-beta-CD increased the bioavailability of cilostazol with low variability in the absorption. Among all cilostazol-cyclodextrins complexes, cilostazol-DM-beta-CD inclusion complex (1:3) prepared by coprecipitation method showed 1.53-fold and 4.11-fold increase in absorption along with 2.1-fold and 2.97-fold increase in dissolution rate in comparison with Pletoz-50 and pure cilostazol, respectively.

Fig. 1

Chemical structure of cilostazol

Fig. 2

a Phase solubility study of cilostazol in HCl buffer at pH 1.2 at 257.2 nm. Key (empty triangles) DM-β-CD; (empty squares) HP-CD; (filled diamonds) β-CD; (empty circles) γ-CD. All values are represented as mean ± SD (±n = 3). b Phase solubility study of cilostazol in water at 257.00 nm. Key (filled triangles) DM-β-CD; (filled squares) HP-CD; (filled diamonds) β-CD; (empty circles) γ-CD. All values are represented as mean ± SD (±n = 3). c Phase solubility study of cilostazol in phosphate buffer at pH 6.8 at 257.8 nm. Key (empty triangles) DM-β-CD; (filled squares) HP-CD; (filled diamonds) β-CD; (empty circles) γ-CD. All values are represented as mean ± SD (±n = 3)

Fig. 3

DSC thermograms of [A] pure cilostazol, [B] pure β-CD, [C] pure γ-CD, [D] pure HP-β-CD, [E] pure DM-β-CD, [F] cilostazol–β-CD physical mixture (1:3), [G] cilostazol–β-CD inclusion complex by coprecipitation method (1:3), [H] cilostazol–β-CD inclusion complex by kneading method (1:3), [I] cilostazol–γ-CD physical mixture (1:3), [J] cilostazol–γ-CD inclusion complex by coprecipitation (1:3), [K] cilostazol–γ-CD inclusion complex by kneading method (1:3), [L] cilostazol–HP-β-CD physical mixture (1:3), [M] cilostazol–HP-β-CD inclusion complex by coprecipitation method (1:3), [N] cilostazol–HP-β-CD inclusion complex by kneading method (1:3), [O] cilostazol–DM-β-CD physical mixture (1:3), [P] cilostazol–DM-β-CD inclusion complex by coprecipitation method (1:3), [Q] cilostazol–DM-β-CD inclusion complex by kneading method (1:3)

Fig. 4

X-ray diffraction patterns of [A] pure β-CD, [B] pure γ-CD, [C] pure HP-β-CD, [D] pure DM-β-CD, [E] pure cilostazol, [F] cilostazol–β-CD physical mixture (1:3), [G] cilostazol–β-CD inclusion complex (1:3), [H] cilostazol–γ-CD physical mixture (1:3), [I] cilostazol–γ-CD inclusion complex (1:3), [J] cilostazol–HP-β-CD physical mixture (1:3), [K] cilostazol–HP-β-CD inclusion complex (1:3), [L] cilostazol–DM-β-CD physical mixture (1:3), [M] cilostazol–DM-β-CD inclusion complex (1:3)

Fig. 5

Cumulative percent drug released from cilostazol–DM-β-CD inclusion complex (1:3) by coprecipitation method for stability study at different time intervals. The results are mean values ± SD derived from three different experimental batches

Fig. 6

Comparison of pharmacokinetic profiles of pure cilostazol, conventional tablet, and cilostazol–DM-β-CD inclusion complex