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Safe and Effective Permeation Enhancers for Oral Drug Delivery

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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.

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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

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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.

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Authors and Affiliations

  1. Department of Chemical Engineering, University of California, Santa Barbara, California, 93106-5080, USA

    Kathryn Whitehead, Natalie Karr & Samir Mitragotri

Authors
  1. Kathryn Whitehead
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  2. Natalie Karr
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  3. Samir Mitragotri
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Corresponding author

Correspondence to Samir Mitragotri.

Electronic supplementary material

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Table SI

Macroscopic Property Data for all CPEs (DOC 193 kb)

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Whitehead, K., Karr, N. & Mitragotri, S. Safe and Effective Permeation Enhancers for Oral Drug Delivery. Pharm Res 25, 1782–1788 (2008). https://doi.org/10.1007/s11095-007-9488-9

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  • DOI: https://doi.org/10.1007/s11095-007-9488-9

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