Safe and effective permeation enhancers for oral drug delivery.
OBJECTIVE
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.
Whitehead
Kathryn
K
Department of Chemical Engineering, University of California, Santa Barbara, California 93106-5080, USA.
Karr
Natalie
N
Mitragotri
Samir
S
D018938:Caco-2 Cells; D016503:Drug Delivery Systems; D017097:Electric Impedance; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005079:Excipients / Q000494:pharmacology* / Q000633:toxicity*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D010539:Permeability / Q000187:drug effects; D013268:Stimulation, Chemical; D013778:Tetrazolium Salts; D013844:Thiazoles
D005079:Excipients; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue