title: Investigation of alternative organic solvents and methods for the preparation of long-circulating and pH-sensitive liposomes containing cisplatin.
abstract: Recent studies using long-circulating and pH-sensitive liposomes containing cisplatin (SpHL-CDDP) have resulted in a formulation with improved pharmacokinetic, toxicity and tumor localization properties. In this study, SpHL-CDDP were prepared in both laboratory and pilot scales. This study evaluated the possibility of using the dehydration-rehydration method, as well as using alternative organic solvents (ethyl acetate/ethanol mixtures at 2:1 and 1:1 volume ratios), for the preparation of liposomes by the reverse-phase evaporation (REV) method. The influence of different concentrations of cisplatin (CDDP) (2.0, 1.0, 0.5 and 0.25 mg/mL) on the entrapment percentage and size of SpHL-CDDP was also investigated. In addition, carbohydrates were tested as cryoprotectants in a freeze-thaw study as a pretest to screen the type to be used in the freeze-drying process. A decrease in the encapsulation percentage of CDDP and an increase in the vesicle diameter could be observed for both liposome formulations prepared with ethyl acetate:ethanol mixtures, as compared with REV liposomes prepared with ethyl ether. It is important to note that after applying either quick or slow cooling, the mean diameter of SpHL (empty liposomes) proved to be similar when in the presence of cryoprotectants. In sum, the optimal processing conditions were achieved when using a 0.5 mg/mL CDDP solution, ethyl ether and the REV method, resulting in liposomal dispersions of mean diameters and homogeneities that were deemed suitable for intravenous administration.
authors: Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brasil.
authors: Cristiane dos Santos
authors: Cdos S
authors: Giuberti
authors: Fernanda Alves
authors: FA
authors: Boratto
authors: Ghania
authors: G
authors: Degobert
authors: Josianne Nicácio
authors: JN
authors: Silveira
authors: Mônica Cristina
authors: MC
authors: Oliveira
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003451:Cryoprotective Agents / Q000494:pharmacology; D000431:Ethanol / Q000737:chemistry / Q000494:pharmacology; D004986:Ether / Q000737:chemistry / Q000494:pharmacology; D005612:Freeze Drying; D008081:Liposomes / Q000138:chemical synthesis; D010316:Particle Size; D010714:Phosphatidylethanolamines / Q000008:administration & dosage; D010865:Pilot Projects; D011092:Polyethylene Glycols / Q000008:administration & dosage; D012997:Solvents / Q000494:pharmacology*
chemical_list: C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D000085:Acetates; D003451:Cryoprotective Agents; D008081:Liposomes; D010714:Phosphatidylethanolamines; D012997:Solvents; D004986:Ether; D000431:Ethanol; D011092:Polyethylene Glycols; C007650:ethyl acetate; D002945:Cisplatin