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Strategies to Maximize Liposomal Drug Loading for a Poorly Water-soluble Anticancer Drug

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Abstract

Purpose

To develop a liposomal system with high drug loading (DL) for intravenous (i.v.) delivery of a poorly water-soluble basic drug, asulacrine (ASL).

Methods

A thin-film hydration and extrusion method was used to fabricate the PEGylated liposomal membranes followed by a freeze and thaw process. A novel active drug loading method was developed using ammonium sulphate gradient as an influx driving force of ASL solubilized with sulfobutyl ether-β-cyclodextrin (SBE-β-CD). DL was maximized by optimizing liposomal preparation and loading conditions. Pharmacokinetics was evaluated following i.v. infusion in rabbits.

Results

Freeze-thaw resulted in unilamellar liposome formation (180 nm) free of micelles. Higher DL was obtained when dialysis was used to remove the untrapped ammonium sulphate compared to ultracentrifuge. The pH and SBE-β-CD level in the loading solution played key roles in enhancing DL. High DL ASL-liposomes (8.9%w/w, drug-to-lipid mole ratio 26%) were obtained with some drug “bundles” in the liposomal cores and were stable in a 5% glucose solution for >80 days with minimal leakage (<2%). Surprisingly, following administration of ASL-liposomes prepared with or without SBE-β-CD, the half-lives were similar to the drug solution despite an increased area under the curve, indicating drug leakage from the carriers.

Conclusions

High liposomal DL was achieved with multiple strategies for a poorly-water soluble weak base. However, the liposomal permeability needed to be tailored to improve drug retention.

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Abbreviations

ASL:

Asulacrine

ASL-L:

Asulacrine liposomes

Cryo-TEM:

Cryo-Transmission electron microscopy

DL:

Drug loading

DLS:

Dynamic light scattering

EE:

Entrapment efficiency

EPR:

Enhanced permeability and retention

PDI:

Polydispersity index

PEG:

Polyethylene glycol

PIP:

Post-injection precipitation

RES:

Reticuloendothelial system

SBE-β-CD:

Sulfobutyl ether-β-cyclodextrin

TFH:

Thin-film hydration

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Acknowledgemnts and Disclosures

This study is a New Zealand-China Research Alliance Project funded by the New Zealand Ministry of Science and Innovation (MSI) (UOAX1102) and International Science and Technology Cooperation Program of China (2011DFG33380). The consumables were supported by a Faculty Research Development Fund from the University of Auckland to Dr Zimei Wu.

The authors declare that they have no conflicts of interest to disclose.

Author information

Authors and Affiliations

  1. School of Pharmacy, The University of Auckland, 1142, Auckland, New Zealand

    Wenli Zhang, James R. Falconer, John P. Shaw, Hongtao Xu, Esther See & Zimei Wu

  2. China Pharmaceutical University, 210009, Nanjing, People’s Republic of China

    Wenli Zhang, Guangji Wang, Jianping Liu, Jianguo Sun & Jiye Aa

  3. Auckland Cancer Society Research Centre, The University of Auckland, 1142, Auckland, New Zealand

    Bruce C. Baguley

Authors
  1. Wenli Zhang
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  2. Guangji Wang
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  4. Bruce C. Baguley
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  6. Jianping Liu
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  8. Esther See
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  11. Zimei Wu
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Correspondence to Jianping Liu or Zimei Wu.

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Zhang, W., Wang, G., Falconer, J.R. et al. Strategies to Maximize Liposomal Drug Loading for a Poorly Water-soluble Anticancer Drug. Pharm Res 32, 1451–1461 (2015). https://doi.org/10.1007/s11095-014-1551-8

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  • DOI: https://doi.org/10.1007/s11095-014-1551-8

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