Pharmaceutical Research

, Volume 25, Issue 8, pp 1782–1788 | Cite as

Safe and Effective Permeation Enhancers for Oral Drug Delivery

  • Kathryn Whitehead
  • Natalie Karr
  • Samir Mitragotri
Research Paper

Abstract

Purpose

The use of intestinal permeation enhancers to overcome the absorption challenges associated with oral drug delivery has been hampered by the notion that enhancer efficacy is directly linked to toxicity. This study attempts to gain insight into the principles governing the potency and toxicity behavior of enhancers.

Methods

Fifty-one enhancers were selected from 11 chemical categories and their potency and toxicity were analyzed in Caco-2 monolayers at concentrations spanning three orders of magnitude.

Results

A small but significant fraction of the 153 enhancer formulations studied demonstrated unexpected but desired behavior, that is, substantial efficacy without marked toxicity. Our results revealed that both chemical category and concentration proved critical in determining the usefulness of many enhancers, and the concept of an enhancer’s ‘therapeutic window’ is discussed. Several of the most promising enhancers identified by the study were tested for their effect on the transport of the marker molecules mannitol and 70 kDa dextran across Caco-2 cells and were capable of increasing permeability more than 10-fold.

Conclusions

The results presented here underscore the potential of chemical permeation enhancers while providing valuable direction as to what classes and concentrations of compounds are of interest when searching for safe and effective additions to oral formulations.

Key words

Caco-2 oral delivery permeation enhancers potency toxicity 

Abbreviations

AS

anionic surfactant

BS

bile salt

CPE

chemical permeation enhancer

CS

cationic surfactant

DMEM

Dulbecco’s Modified Eagles Medium

EP

enhancement potential

FA

fatty acid

FE

fatty ester

FM

fatty amine

MTT

methyl thiazole tetrazolium

NR

nitrogen-containing ring

NS

nonionic surfactant

OP

overall potential

OT

other

PPZ

phenyl piperazine

SDC

sodium deoxycholate

SLA

sodium laureth sulfate

SOA

sodium salt of oleic acid

SS

sodium salt of fatty acid

TEER

transepithelial electrical resistance

TP

toxicity potential

ZS

zwitterionic surfactant

Notes

Acknowledgements

This work was supported by a fellowship to KW from the Graduate Research and Education in Adaptive bio-Technology (GREAT) Training Program by the University of California Biotechnology Research and Education Program and by the American Diabetes Association.

Supplementary material

11095_2007_9488_MOESM1_ESM.doc (194 kb)
Table SIMacroscopic Property Data for all CPEs (DOC 193 kb)

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Kathryn Whitehead
    • 1
  • Natalie Karr
    • 1
  • Samir Mitragotri
    • 1
  1. 1.Department of Chemical EngineeringUniversity of CaliforniaSanta BarbaraUSA

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