Effect of liposomes on the rate of alkaline hydrolysis of indomethacin andacemetacin

The anti-inflammatory, analgesic, and antipyretic drugs indomethacin (INDO) and acemetacin (ACE), extensively used for the treatment of diseases of de generative or inflammatory character, exhibit marked gastric irritant actio n, have low water solubility at neutral pH, and decompose in alkali. Altern ative formulations are being investigated to obtain products with lower tox icity and higher stability. Here we examine the effect of liposome charge o n the rate of alkaline decomposition of INDO and ACE using micelles as refe rence. Binding of ACE and INDO to zwitterionic hexadecylphosphocholine (HDP C) micelles and phosphatidylcholine (PC) liposomes was analyzed using a two -phase separation model to quantify the effect of these aggregates on the r ate of alkaline degradation. The substrate association constants to HDPC mi celles were 1335 and 2192 M-1 for INDO and ACE, respectively, whereas the c orresponding values for PC vesicles were 612 and 3050 M-1. The difference w as attributed to the additional hydrophobicity of ACE. The inhibitory effec t of HDPC micelles and PC vesicles was quantified by calculating the ratio between the rate constants in water (k(w)) and in the aggregate (k(m)). The values of the k(w)/k(m) ratios for INDO and ACE in HDPC micelles were, res pectively, 80 and 42, and in PC liposomes these ratios were 21 and 3.7, res pectively. Positively charged micelles of hexadecyltrimethylammonium chlori de (CTAC) and vesicles containing varying proportions of dioctadecyldimethy lammonium chloride (DODAC) and PC increase the rate of INDO and ACE alkalin e decomposition. Vesicle effects were very sensitive to the DODAC/PC ratio, with rates increasing with the proportion of DODAC. The data were analyzed quantitatively using a pseudophase model with explicit consideration of io n exchange. The calculated second-order rate constants in micelles and vesi cles were lower than that in water. The charge density in the liposome nece ssary to increase the entrapment efficiency and decrease drug decomposition can be modulated, by judicious choice of pH and ionic strength. These mani pulations can lead to more stable formulation with increased efficiency in drug entrapment and controlled effects on drug stability. (C) 2001 Wiley-Li ss, Inc.