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 MitragotriEmail author
Research Paper



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.


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.


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.


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 



anionic surfactant


bile salt


chemical permeation enhancer


cationic surfactant


Dulbecco’s Modified Eagles Medium


enhancement potential


fatty acid


fatty ester


fatty amine


methyl thiazole tetrazolium


nitrogen-containing ring


nonionic surfactant


overall potential




phenyl piperazine


sodium deoxycholate


sodium laureth sulfate


sodium salt of oleic acid


sodium salt of fatty acid


transepithelial electrical resistance


toxicity potential


zwitterionic surfactant



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 SI Macroscopic Property Data for all CPEs (DOC 193 kb)


  1. 1.
    M. Goldberg, and I. Gomez-Orellana. Challenges for the oral delivery of macromolecules. Nat. Rev. Drug Discov. 2:289–295 (2003).PubMedCrossRefGoogle Scholar
  2. 2.
    G. Mustata, and S.M. Dinh. Approaches to oral drug delivery for challenging molecules. Crit. Rev. Ther. Drug Carrier Syst. 23:111–135 (2006).PubMedGoogle Scholar
  3. 3.
    L. Serra, J. Domenech, and N. A. Peppas. Drug transport mechanisms and release kinetics from molecularly designed poly(acrylic acid-g-ethylene glycol) hydrogels. Biomaterials. 27:5440–5451 (2006).PubMedCrossRefGoogle Scholar
  4. 4.
    S. L. Tao, and T. A. Desai. Gastrointestinal patch systems for oral drug delivery. Drug Discov. Today. 10:909–915 (2005).PubMedCrossRefGoogle Scholar
  5. 5.
    B. J. Aungst. Intestinal permeation enhancers. J. Pharm. Sci. 89:429–442 (2000).PubMedCrossRefGoogle Scholar
  6. 6.
    N. N. Salama, N. D. Eddington, and A. Fasano. Tight junction modulation and its relationship to drug delivery. Adv. Drug Deliv. Rev. 58:15–28 (2006).PubMedCrossRefGoogle Scholar
  7. 7.
    D. Bourdet, G. Pollack, and D. Thakker. Intestinal absorptive transport of the hydrophilic cation ranitidine: a kinetic modeling approach to elucidate the role of uptake and efflux transporters and paracellular vs. transcellular transport in Caco-2 Cells. Pharm. Res. 23:1178–1187 (2006).PubMedCrossRefGoogle Scholar
  8. 8.
    E. S. Swenson, W. B. Milisen, and W. Curatolo. Intestinal permeability enhancement: efficacy, acute local toxicity, and reversibility. Pharm Res. 11:1132–1142 (1994).PubMedCrossRefGoogle Scholar
  9. 9.
    R. Konsoula, and F. A. Barile. Correlation of in vitro cytotoxicity with paracellular permeability in Caco-2 cells. Toxicol. In Vitro. 19:675–684 (2005).PubMedCrossRefGoogle Scholar
  10. 10.
    P. Karande, A. Jain, and S. Mitragotri. Relationships between skin's electrical impedance and permeability in the presence of chemical enhancers. J. Control. Rel. 110:307–313 (2006).CrossRefGoogle Scholar
  11. 11.
    M. Tomita, M. Hayashi, and S. Awazu. Absorption-enhancing mechanism of EDTA, caprate, and decanoylcarnitine in Caco-2 cells. J. Pharm. Sci. 85:608–611 (1996).PubMedCrossRefGoogle Scholar
  12. 12.
    E. Fuller, C. Duckham, and E. Wood. Disruption of epithelial tight junctions by yeast enhances the paracellular delivery of a model protein. Pharm. Res. 24:37–47 (2007).PubMedCrossRefGoogle Scholar
  13. 13.
    E. S. Swenson, and W. Curatolo. Intestinal permeability enhancement for proteins, peptides, and other polar drugs: mechanisms and potential toxicity. Adv. Drug Deliv. Rev. 8:39–92 (1992).CrossRefGoogle Scholar
  14. 14.
    N. Frank, H. Achim, S.-H. Georg von, and M. Heinz. Synergistic action of a cyclic depsipeptide and piperazine on nematodes. Pharm. Res. 86:982–992 (2000).Google Scholar
  15. 15.
    J. S. Warrington, L. L. Von Moltke, J. S. Harmatz, R. I. Shader, and D. J. Greenblatt. The effect of age on sildenafil biotransformation in rat and mouse liver microsomes. Drug Metabol. Dispos. 31:1306–1309 (2003).CrossRefGoogle Scholar
  16. 16.
    M. J. Fray, G. Bish, P. V. Fish, A. Stobie, F. Wakenhut, and G. A. Whitlock. Structure-activity relationships of N-substituted piperazine amine reuptake inhibitors. Bioorg. Med. Chem. Lett. 16:4349–4353 (2006).PubMedCrossRefGoogle Scholar
  17. 17.
    K. Whitehead, Z. Shen, and S. Mitragotri. Oral delivery of macromolecules using intestinal patches: applications for insulin delivery. J. Control. Rel. 98:37–45 (2004).CrossRefGoogle Scholar
  18. 18.
    E. Duizer, C. Van Der Wulp, C. H. M. Versantvoort, and J. P. Groten. Absorption enhancement, structural changes in tight junctions and cytotoxicity caused by palmitoyl carnitine in Caco-2 and IEC-18 cells. J. Pharmacol. Exp. Ther. 287:395–402 (1998).PubMedGoogle Scholar
  19. 19.
    S. Takatsuka, T. Kitazawa, T. Morita, Y. Horikiri, and H. Yoshino. Enhancement of intestinal absorption of poorly absorbed hydrophilic compounds by simultaneous use of mucolytic agent and non-ionic surfactant. Eur. J. Pharm. Biopharm. 62:52–58 (2006).PubMedCrossRefGoogle Scholar
  20. 20.
    K. Lindhardt, and E. Bechgaard. Sodium glycocholate transport across Caco-2 cell monolayers, and the enhancement of mannitol transport relative to transepithelial electrical resistance. Int. J. Pharm. 252:181–186 (2003).PubMedCrossRefGoogle Scholar
  21. 21.
    T. Lindmark, T. Nikkila, and P. Artursson. Absorption enhancement through intracellular regulation of tight junction permeability by medium chain fatty acids in Caco-2 cells. J. Pharmacol. Exp. Ther. 284:362–369 (1998).PubMedGoogle Scholar
  22. 22.
    R. B. Shah, A. Palamakula, and M. A. Khan. Cytotoxicity evaluation of enzyme inhibitors and absorption enhancers in Caco-2 cells for oral delivery of salmon calcitonin. J. Pharm. Sci. 93:1070–1082 (2004).PubMedCrossRefGoogle Scholar
  23. 23.
    M. A. Radwant, and H. Y. Aboul-Enein. The effect of oral absorption enhancers on the in vivo performance of insulin-loaded poly(ethylcyanoacrylate) nanospheres in diabetic rats. J. Microencapsul. 19:225–235 (2002).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

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

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