2-Hydroxypropyl-ß-Cyclodextrin Complex with Ketotifen Fumerate for Eye Drops Preparations

Ketotifen fumerate ophthalmic solution is an antihistaminic drug. The aim of this study was to develop a novel aqueous ketotifen eye drop formulation containin ketotifen/2-Hydroxypropyl-β-cyclodextrin complex, which has the ability to enhance the solubility of the drug at the physiological pH (7.4), consequently decreasing the irritation to the eye. Moreover, increaseing the fraction of the unionized drug leads to enhancing the permeability of the drug through the cornea. The stability constant was determined from phase-solubility diagrams and found to be higher with KF/HP-ß-CD complex (29.47 M−1) than KF/ß-CD complex (10.36 M−1). Differential scanning calorimetry (DSC), fourier transform-infrared (FT-IR) spectroscopy and X-ray analysis (X-ray) showed the formation and the physiochemical proporties of the complex. The effect of different additives including; antioxidants, isotonicity adjusting agents and preservatives on the stability of ketotifen fumerate solution were studied. Sodium ascorbate (0.1%w/v) showed a significant increase in the stability of the KF solutoion. Fluid thioglycolate medium and Tryptic Soy Broth were used as a medium to test of sterility of selected formulations to detect aerobic, anaerobic and fungal contamination and verified that no turbidity or surface growth was observed during the incubation period of all tested formulae. Finally, the chemical stability using the stability indicating HPLC assay showed that the stability of the selected formulation were significantly higher in comparison to that of a commercial product (Zaditen® eye drops Novartis Pharma-Egypt) (p>0.05). These results indicate that KF/HP-ß-CD eye drops formulation is a promising (formulation) resulting in enhancing the solability, stability and permeability of the drug.Keywords: Ketotifen Fumerate; 2-Hydroxypropyl-ß-cyclodextrin; Inclusion complex; Solubility; Stability