LARGE-SCALE PRODUCTION OF LIPOSOMES CONTAINING MONOMERIC ZINC PHTHALOCYANINE BY CONTROLLED DILUTION OF ORGANIC-SOLVENTS

This work describes the development of an organic solvent dilution met hod suitable for the large scale manufacturing of small unilamellar li posomes containing the water-insoluble photosensitizer zinc phthalocya nine in the monomeric state. N-Methyl pyrrolidone (NMP)/tert-butyl alc ohol was selected as water miscible organic phase in which the phospho lipids 1-palmitoyl, 2-oleoylphosphatidylcholine (POPC), and 1,2-dioelo ylphosphatidylserine (OOPS) and the dye were dissolved. This organic p hase was mixed with an excess of a water phase using a dynamic mixing device, yielding reproducibly unilamellar liposomes with a mean size o f 50-150 nm as measured with quasielastic light scattering. After conc entration, the organic solvents were efficiently removed by cross-flow filtration. The liposomes were then sterile filtered and freeze-dried . A method to measure the aggregation state of the dye in the liposome s was developed. A stable lyophilized formulation containing monomeric liposomal ZnPc could be obtained by using a solution of ZnPc in NMP ( 2 mg/mL) and ZnPc/phospholipid (1:100 w/w ratio) and performing concen tration and dialysis at 4 degrees C and lyophilization in presence of a mixture of lactose and phospholipid (5:1 w/w ratio).