Physicochemical specification of drug carrying liposomes for the quality control in the industrial production

Abstract

Animal data of liposomal drugs in a laboratory environment are often not reproduced on industrial scale products. One of the most important reasons is in the fact that the colloid-chemical properties of the liposomes manufactured on a small scale are not reproduced in a large scale production. In this review, colloid chemical characterization of liposomes is introduced, fixed aqueous layer thickness (FALT) as an example, and its importance in a quality control of a liposomal product in an industrial scale production is shown. Methoxy-polyethylenglycol-diacylgricerol (PEG-DAG) with varying PEG chain length and acyl chains were synthesized, FALT of liposomes coated with PEG-DAG determined and tissue distribution in tumor bearing mice studied. The higher incorporation ratio of PEG-DAG into liposomal membrane was observed with PEG-DAG with short acyl chains (myristoyl) and a small PEG molecular weight (1000). The easier to be incorporated, the easier to be stripped in the serum. The disposition data in the mice well reflected the colliod chemical and in vitro data of the PEG liposomes. Galactosyl-carbonyl-propionyl-polyethyleneglycol-diacylglycerol (Gal-PEG-DAG) with oxyethylene number, n=10, 20 and 40 were synthesized. The exposure of galactosy residue beyond the fixed aqueous layer of liposomes coated with Gal-PEG-DAG was monitored by RCA lectin induced agglutination, half life in the blood and organ distribution after i.v. injection into rats determined and intrahepatic distribution studied. Only the liposomes containing Gal-PEG 10DAG aggregated with the lectin, indicating that only with this derivative the galactose group was adequately exposed. The Gal-PEG 10-DAG liposomes were cleared from plasma with a half life of 0.3 h. The plasma elimination could be attributed entirely to increased uptake by the liver. The increased liver uptake was almost entirely attributed to increased uptake by the non-parenchymal cell. Incorporation of PEG-DSPE in the Gal-PEG 10DAG liposomes caused (1) a 3-fold increase in blood circulation time, (2) a small but significant decrease in hepatic uptake after 20 h and (3) a significant shift in intrahepatic distribution in favor of the hepatocytes, comparable to that of the control liposomes. In conclusion, therapeutic efficacy and safety of liposomes can be controlled by their colloid chemical, more exactly, surface chemical properties. By setting up reasonable quality control specifications of the properties in the laboratory and examining the specifications satisfied in upscaling, the efficacy and safety are reproduced in a large scale product.