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22017_ftp.pdf
A Mathematical Relationship for Hydromorphone Loading into
Liposomes with Trans-Membrane Ammonium Sulfate Gradients
SHENG TU,1 TAMARA MCGINNIS,1 LISA KRUGNER-HIGBY,2 TIMOTHY D. HEATH1
1School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705
2School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53705
Received 4 August 2009; revised 12 October 2009; accepted 15 October 2009
Published online 3 December 2009 in Wiley InterScience (). DOI 10.1002/jps.22017
ABSTRACT: We have studied the loading of the opioid hydromorphone into liposomes using
ammonium sulfate gradients. Unlike other drugs loaded with this technique, hydromorphone is
freely soluble as the sulfate salt, and, consequently, does not precipitate in the liposomes after
loading. We have derived a mathematical relationship that can predict the extent of loading
based on the ammonium ion content of the liposomes and the amount of drug added for loading.
We have adapted and used the Berthelot indophenol assay to measure the amount of ammonium
ions in the liposomes. Plots of the inverse of the fraction of hydromorphone loaded versus the
amount of hydromorphone added are linear, and the slope should be the inverse of the amount of
ammonium ions present in the liposomes. The inverse of the slopes obtained closely correspond
to the amount of ammonium ions in the liposomes measured with the Berthelot indophenol
assay. We also show that loading can be less than optimal under conditions where osmotically
driven loss of ammonium ions or leakage of drug after loading may occur. 2009 Wiley-Liss, Inc.
and the American Pharmacists Association J Pharm Sci 99:2672–2680, 2010
Keywords: liposomes; microencapsulation; encapsulation; controlled rel
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