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Investigation of alternative organic solvents and methods for the preparation of long-circulating and pH-sensitive liposomes containing cisplatin.

Journal of liposome research (2013-05-11)
Cristiane dos Santos Giuberti, Fernanda Alves Boratto, Ghania Degobert, Josianne Nicácio Silveira, Mônica Cristina Oliveira
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.

MATERIALS
Product Number
Brand
Product Description

Supelco
Ethyl acetate solution, certified reference material, 2000 μg/mL in methanol
Sigma-Aldrich
Diethyl ether, contains BHT as inhibitor, puriss. p.a., ACS reagent, reag. ISO, reag. Ph. Eur., ≥99.8%
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Diethyl ether, puriss., contains ~5 mg/L 2,6-di-tert.-butyl-4-methylphenol as stabilizer, meets analytical specification of Ph. Eur., BP, ≥99.5% (GC)
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Diethyl ether, ACS reagent, anhydrous, ≥99.0%, contains BHT as inhibitor
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Ethyl acetate, ReagentPlus®, ≥99.8%
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Ethyl acetate, anhydrous, 99.8%
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Ethyl acetate, ≥99%, FCC, FG
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Ethyl acetate, natural, ≥99%, FCC, FG
Supelco
Ethyl acetate, analytical standard
Supelco
Ethyl ether solution, certified reference material, 2000 μg/mL in methanol
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Ethyl acetate, suitable for HPLC, ≥99.7%
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Ethyl acetate, suitable for HPLC, ≥99.8%
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Ethyl acetate, HPLC Plus, for HPLC, GC, and residue analysis, 99.9%
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Ethyl acetate, puriss., meets analytical specification of Ph. Eur., BP, NF, ≥99.5% (GC)
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Ethyl acetate, ACS reagent, ≥99.5%
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Ethyl acetate, ACS reagent, ≥99.5%
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Ethyl acetate, puriss. p.a., ACS reagent, reag. ISO, reag. Ph. Eur., ≥99.5% (GC)
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Ethyl acetate, biotech. grade, ≥99.8%