Capacity of cholesteryl hemisuccinate in ion pair/phospholipid complex to improve drug-loading, stability and antibacterial activity of clarithromycin intravenous lipid microsphere.

Current research was to evaluate the capacity and molecular interaction of ion pair/phospholipid complex during preparation of clarithromycin intravenous lipid microsphere (CLA-LM) for improving drug-loading, stability and antibacterial activity. The optimum pH range for the presence of ion pair formed by CLA and cholesteryl hemisuccinate (CHEMS) was found to be between 6.4 and 8.2. CLA-LM prepared by ion pair/phospholipid complex possessed improved drug-loading (5-10 mg/ml), plasma stability, storage stability (24 months at 4 ± 2℃) and better activity for multi-drug-resistant Mycobacterium tuberculosis (MIC = 0.058 μg/ml). The release profile in vitro was pH-sensitive and greater in more acidic condition, which was effective for pathological targeting. CLA-LM presented controlled release and low drug leakage in plasma. Langmuir monolayer showed that the incorporation of CHEMS obviously improved interfacial molecular interactions of the mixed monolayer. The ordering and condensing effect of CHEMS resulted in higher collapse surface pressure and smaller limiting area, as well as reduced compression modulus. Close aggregate network distribution with particular micro domains in atomic force microscopy images reflected the enhanced miscibility and thermodynamic stability. The change of the spatial location and protonation degree of CHEMS resulted from the aqueous subphase pH value from 6 to 8 was observed. More acidic environment allowed for better molecular interaction and interface behavior. These results indicated that CHEMS enhances the phospholipid packing to achieve stable CLA-encapsulation in phospholipid interface and identify the preference of ion pair/phospholipid complex as a valuable delivery strategy to develop CLA formulations for improving drug-loading, stability and antibacterial activity.