Preparation and pharmacodynamic evaluation of liposomes of indomethacin

The side effects of indomethacin, such as ulceration of the kidney and cent ral nervous system (CNS) toxicity, limit its use as a drug for rheumatoid a rthritis. Encapsulation of this drug in liposomes may reduce the toxic effe cts. The aim of this study was to determine the factors influencing encapsu lation of indomethacin in liposomes and to determine anti-inflammatory pote ntial of liposomal indomethacin. A series of liposomal formulations of indo methacin were prepared using various phospholipids. The effects of method o f preparation, lipid composition, charge, and cholesterol (CH) on encapsula tion of indomethacin in liposomes were investigated A significant variation in encapsulation of the drug in liposomes was observed when prepared by di fferent methods. With all the methods of preparation tried, the favorable l ipid composition for high encapsulation of this drug was egg phosphatidyl c holine: CH: stearlyamine (PC: CH: SA) at a 1: 05: 0.1 molar ratio. Inclusio n of cholesterol did not affect the encapsulation efficiency of the drug in liposomes. The drug release profile from the liposomes was biphasic, and t he highest percentage drug release was observed with large unilamellar vesi cles (LUVs) (100 nm). Inclusion of stearylamine (PC: CH: SA 1: 0.5: 0.1) an d phosphatidyl glycerol (PG) (PC: CH: PG 1: 0.5: 0.2) in the liposomes redu ced the release of the drug in comparison to the neutral liposomes (PC: CH 1:1). The slow release of the drug from stearylamine-containing liposomes m ay be explained by the electrostatic interaction between the acid moiety of the drug and the amine moiety of the lipid. It is assumed that the possibl e hydrogen bonding between -OH groups of phosphatidyl glycerol and the -COO H group of the drug might be the reason for the slow release of the drug fr om PC: CH: PG (1: 0.5: 0.2) containing liposomes. Pharmacodynamic evaluatio n of the liposomes was performed by carrageenan-induced rat paw edema (acut e) and adjuvant arthritis (chronic) models. The anti-inflammatory activity was increased from the first to fifth hour PC: CH: PG (1: 0.5: 0.2) and PC: CH: SA (1: 0.5: 0.1) liposomes showed the highest percentage inhibition of edema. In both these models, anti-inflammatory activity of liposomal indom ethacin was significantly higher than that of free indomethacin (p < .01). The ulcer Elder of the free drug was about three rimes more than the encaps ulated drug when administered at the same dose intraperitoneally to arthrit ic rats consecutively for 21 days.