Encapsulation of Azithromycin Ion Pair in Liposome for Enhancing Ocular Delivery and Therapeutic Efficacy on Dry Eye

The aim of this work was to design a novel ocular delivery carrier based on liposomes loaded with azithromycin (AZM) for the treatment of dry eye (DE) disease. To improve the drug loading efficiency, an AZM-cholesteryl hemisuccinate (CHEMS) ion pair (ACIP) was first prepared, and the successful formation of the ACIP was characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRD), which demonstrated a stable interaction between CHEMS and AZM. The ACIP-loaded liposome (ACIP-Lip) appeared as spherical particles under TEM, with a uniform particle size of 60 +/- 2 nm and zeta potential of -20.3 +/- 4.6 mV. The entrapment efficiency (EE) and drug loading (DL) of ACIP-Lip were greatly improved to 95.6 +/- 2.0 and 9.2 +/- 0.7%, respectively, which was attributed to the enhanced loading capacity of the liposomes through use of the ion pair and addition of MCT. ACIP-Lip also exhibited a high stability during a 3 month storage period at both 4 and 25 degrees C. In vitro release of AZM from ACIP-Lip was pH-dependent, with a more rapid release at pH 6.0 than at pH 7.4, which is beneficial for ocular therapy. Furthermore, the corneal permeation of AZM was enhanced by ACIP-Lip, demonstrating an apparent permeability coefficient (P-app x 10(6)) of 8.92 +/- 0.56 cm/s, which was approximately 2-fold greater that of the AZM solution. Finally, an in vivo pharmacodynamical study showed that the essential symptoms of DE rats were significantly improved by ACIP-Lip, as it was highly efficient and superior compared to hyaluronic acid sodium eye drops available on the market. Hence, ACIP-Lip is a promising formulation for DE treatment.