title: Large-scale production of liposomes containing monomeric zinc phthalocyanine by controlled dilution of organic solvents.
abstract: This work describes the development of an organic solvent dilution method suitable for the large scale manufacturing of small unilamellar liposomes containing the water-insoluble photosensitizer zinc phthalocyanine in the monomeric state. N-Methyl pyrrolidone (NMP)/tert-butyl alcohol was selected as water miscible organic phase in which the phospholipids 1-palmitoyl, 2-oleoylphosphatidylcholine (POPC), and 1,2-dioeloylphosphatidylserine (OOPS) and the dye were dissolved. This organic phase was mixed with an excess of a water phase using a dynamic mixing device, yielding reproducibly unilamellar liposomes with a mean size of 50-150 nm as measured with quasielastic light scattering. After concentration, 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 liposomes 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 concentration and dialysis at 4 degrees C and lyophilization in presence of a mixture of lactose and phospholipid (5:1 w/w ratio).
authors.affiliation: Research and Development Department Ciba-Geigy Ltd., Basle, Switzerland.
authors.forename: U
authors.initials: U
authors.lastname: Isele
authors.forename: P
authors.initials: P
authors.lastname: van Hoogevest
authors.forename: R
authors.initials: R
authors.lastname: Hilfiker
authors.forename: H G
authors.initials: HG
authors.lastname: Capraro
authors.forename: K
authors.initials: K
authors.lastname: Schieweck
authors.forename: H
authors.initials: H
authors.lastname: Leuenberger
mesh_terms: D002849:Chromatography, Gas; D003956:Dialysis; D004337:Drug Carriers / Q000138:chemical synthesis*; D004339:Drug Compounding; D004355:Drug Stability; D005374:Filtration; D005612:Freeze Drying; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry*; D054833:Isoindoles; D008081:Liposomes / Q000138:chemical synthesis*; D009682:Magnetic Resonance Spectroscopy; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000737:chemistry*; D010316:Particle Size; D010743:Phospholipids / Q000737:chemistry; D012995:Solubility; D012997:Solvents; D015032:Zinc / Q000008:administration & dosage / Q000737:chemistry*; D017967:Zinc Compounds
chemical_list: D004337:Drug Carriers; D007211:Indoles; D054833:Isoindoles; D008081:Liposomes; D009942:Organometallic Compounds; D010743:Phospholipids; D012997:Solvents; D017967:Zinc Compounds; C052159:Zn(II)-phthalocyanine; D015032:Zinc