薬物含有リポソームの工業生産・品質管理のためのコロイド化学的規格設定

抄録

Efficacy and safety data of liposomal drugs in a laboratory environment are often not reproduced on an industrial production scale. This is largely due to the fact that the colloid-chemical properties of the liposomes manufactured on a small scale are not reproduced in large scale production. Though the size and the electric charge of liposomes are measured and are adequately specified in relation to the bio-distributions in most developments of liposomes (1), uniformity of lipid components, exposure of bio-chemically important functional groups on the outer surface of liposomes (2), fixed aqueous layer thickness (FALT), number of the lipid bilayers, etc., are dependent upon the scale of production. Nevertheless these properties are not always exactly specified. Uniformity, especially of the functional groups on the membrane surface can be assesssed chemically or bio-chemically with fractionated samples, and FALT can be easily determined through electro-chemical means (3). In this review, colloid chemical characterization of liposomes is introduced, FALT as an example, and its importance in a quality control of a liposomal product in an industrial scale production is shown. Methoxy-polyethyleneglycol-diacylglycerol (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. 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 incorporate, the easier to be stripped in the serum. The disposition data in the rats well reflected the colloid 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 the galactose residue beyong the fixed aqueous layer of liposomes coated with Gal-PEG-DAG was monitored by a lectin, Ricinus communis agglutinin (RCA) induced agglutination, the half life in the blood after i.v. injection into rats, organ distribution determined and intrahepatic distribution studied. Only the liposomes containing the Gal-PEG₁₀-DAG aggregated with the lectin, indicating that only with this derivative the galactose group was adequately exposed. The Gal-PEG₁₀-DAG liposomes were cleared from the plasma with a half life of 0.3h. 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 to the Gal-PEG₁₀-DAG liposomes caused 1) a three-fold increase in blood circulation time, 2) a small but significant decrease in hepatic uptake after 20h 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 specification of the properties in laboratory and examining the specifications satisfied in upscaling, the efficacy and safety are reproduced in a large scale product.