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Pharmaceutical Research

, Volume 22, Issue 8, pp 1320–1330 | Cite as

Liposomal Formulations of Inflammatory Bowel Disease Drugs: Local versus Systemic Drug Delivery in a Rat Model

  • Filippos Kesisoglou
  • Simon Yuji Zhou
  • Susan Niemiec
  • Jordan Wing Lee
  • Ellen M. Zimmermann
  • David Fleisher
Research Paper

Purpose

Based on adherence to intestinal mucosa, intralumenally administered liposomal formulations of 5-aminosalicylate (5-ASA) and 6-mercaptopurine (6-MP) were studied for their potential to enhance local drug delivery to intestinal tissue for the treatment of inflammatory bowel disease.

Methods

5-ASA was encapsulated in standard phospholipid liposomes while 6-MP required encapsulation in nonphospholipid liposomes to obtain equivalent drug loading. Encapsulation efficiency was measured by size-exclusion chromatography/high-performance liquid chromatogtaphy (HPLC). Liposomal formulations or solution of the drugs were injected into unligated jejunum to compare pharmacokinetics and into ligated loops of rat ileum and colon to evaluate local delivery. Dextran sulfate and acetic acid induced colitis were used as models of lower intestinal inflammation. Plasma, tissue and luminal drug and metabolite levels were measured by liquid scintillation counting or HPLC.

Results

Encapsulation efficiency of 6-MP was dependent on lipid content and composition. While liposomal encapsulation significantly reduced systemic absorption of 5-ASA this was not the case for 6-MP. Liposomal adherence to intestinal tissue resulted in increased tissue levels for 5-ASA; however, 6-MP local tissue levels were not improved compared to solution drug.

Conclusions

Nonphospholipid liposomes optimize encapsulation of 6-MP. While liposomal formulations show potential for local drug delivery to diseased bowel, drug physicochemical properties, absorption, and metabolic profiles dictate tissue-targeting potential. Liposomes reduce systemic availability from paracellular absorption of hydrophilic 5-ASA, but fail to improve local tissue delivery of 6-MP, a molecule absorbed by passive membrane permeation that undergoes extensive first- pass metabolism.

Key Words

absorption drug delivery inflammatory bowel disease intestine liposomes 

Abbreviations

5-ASA

5-aminosalicylate

FBS

fetal bovine serum

GDS

glyceryl distearate

HPLC

high-performance liquid chromatography

IBD

inflammatory bowel disease

IBS

irritable bowel system

6-MP

6-mercaptopurine

NEAA

nonessential amino acids

NMR

nuclear magnetic resonance

PBS

phosphate-buffered saline

POE

polyoxyethylene stearyl ether

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Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Filippos Kesisoglou
    • 1
    • 2
  • Simon Yuji Zhou
    • 1
  • Susan Niemiec
    • 3
  • Jordan Wing Lee
    • 1
  • Ellen M. Zimmermann
    • 2
  • David Fleisher
    • 1
  1. 1.Department of Pharmaceutical Sciences, College of PharmacyThe University of MichiganAnn ArborUSA
  2. 2.Division of Gastroenterology, Department of Internal MedicineThe University of MichiganAnn ArborUSA
  3. 3.Pfizer Global Research and DevelopmentAnn Arbor LaboratoriesAnn ArborUSA

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