title: Post-insertion of poloxamer 188 strengthened liposomal membrane and reduced drug irritancy and in vivo precipitation, superior to PEGylation.
abstract: The ultimate aim of this study was to develop asulacrine (ASL)-loaded long-circulating liposomes to prevent phlebitis during intravenous (i.v.) infusion for chemotherapy. Poly(ethylene)glycol (PEG) and poloxamer 188-modified liposomes (ASL-PEGL and ASL-P188L) were developed, and ASL was loaded using a remote loading method facilitated with a low concentration of sulfobutyl ether-β-cyclodextrin as a drug solubilizer. The liposomes were characterized in terms of morphology, size, release properties and stability. Pharmacokinetics and venous tissue tolerance of the formulations were simultaneously studied in rabbits following one-hour i.v. infusion via the ear vein. The irritancy was assessed using a rat paw-lift/lick model after subplantar injections. High drug loading 9.0% w/w was achieved with no drug leakage found from ASL-PEGL or ASL-P188L suspended in a 5% glucose solution at 30days. However, a rapid release (leakage) from ASL-PEGL was observed when PBS was used as release medium, partially related to the use of cyclodextrin in drug loading. Post-insertion of poloxamer 188 to the liposomes appeared to be able to restore the drug retention possibly by increasing the packing density of phospholipids in the membrane. In rabbits (n=5), ASL-P188L had a prolonged half-life with no drug precipitation or inflammation in the rabbit ear vein in contrast to ASL solution. Following subplantar (footpad) injections in rats ASL solution induced paw-lick/lift responses in all rats whereas ASL-P188L caused no response (n=8). PEGylation showed less benefit possibly due to the drug 'leakage'. In conclusion, drug precipitation in the vein and the drug mild irritancy may both contribute to the occurrence of phlebitis caused by the ASL solution, and could both be prevented by encapsulation of the drug in liposomes. Poloxamer 188 appeared to be able to 'seal' the liposomal membrane and enhance drug retention. The study also highlighted the importance of bio-relevant in vitro release study in formulation screening.
authors.affiliation: School of Pharmacy, The University of Auckland, Private Bag 92019, Auckland, New Zealand; China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Wenli
authors.initials: W
authors.lastname: Zhang
authors.affiliation: China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
authors.affiliation: School of Pharmacy, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: Esther
authors.initials: E
authors.lastname: See
authors.affiliation: School of Pharmacy, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: John P
authors.initials: JP
authors.lastname: Shaw
authors.affiliation: Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Baguley
authors.affiliation: China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: jianping1293@163.com.
authors.forename: Jianping
authors.initials: J
authors.lastname: Liu
authors.affiliation: Anatomy, Medical Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: Satya
authors.initials: S
authors.lastname: Amirapu
authors.affiliation: School of Pharmacy, The University of Auckland, Private Bag 92019, Auckland, New Zealand. Electronic address: z.wu@auckland.ac.nz.
authors.forename: Zimei
authors.initials: Z
authors.lastname: Wu
mesh_terms: D000677:Amsacrine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011232:Chemical Precipitation; D007260:Infusion Pumps / Q000009:adverse effects*; D007267:Injections / Q000009:adverse effects; D008081:Liposomes / Q000737:chemistry*; D008297:Male; D010689:Phlebitis / Q000139:chemically induced / Q000209:etiology* / Q000517:prevention & control; D020442:Poloxamer / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011817:Rabbits; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D000677:Amsacrine; D020442:Poloxamer; D011092:Polyethylene Glycols; C042315:asulacrine
keywords: 1,2-Dipalmitoyl-rac-glycero-3-phosphocholine (CID 6139); 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (CID 406952); Asulacrine (CID 107924); Asulacrine isethionate salt (CID 157348); Cholesterol (CID 5997); Drug retention; Irritation; PEGylated liposomes; Phlebitis; Poloxamer 188; Post-injection precipitation