Advertisement

The AAPS Journal

, Volume 16, Issue 5, pp 1064–1076 | Cite as

Efficacious Intestinal Permeation Enhancement Induced by the Sodium Salt of 10-undecylenic Acid, A Medium Chain Fatty Acid Derivative

  • David J. BraydenEmail author
  • Edwin Walsh
Research Article

ABSTRACT

10-undecylenic acid (UA) is an OTC antifungal therapy and a nutritional supplement. It is an unsaturated medium chain fatty acid (MCFA) derivative, so our hypothesis was that its 11-mer sodium salt, uC11, would improve intestinal permeation similar to the established enhancer, sodium caprate (C10), but without the toxicity of the parent saturated MCFA, decylenic acid (C11). MTT assay and high-content screening (HCS) confirmed a cytotoxicity ranking in Caco-2 cells: C11 > C10 = uC11. Five to ten millimolars of the three agents reduced TEER and increased the Papp of [14C]-mannitol across Caco-2 monolayers and rat intestinal mucosae, a concentration that matched increases in plasma membrane permeability seen in HCS. Although C11 was the most efficacious enhancer in vitro, it damaged monolayers and tissue mucosae more than the other two agents at similar concentrations and exposure times and was therefore not pursued further. Rat jejunal and colonic in situ intestinal instillations of 100 mM C10 or uC11 with FITC-dextran 4000 (FD4) solutions yielded comparable regional enhancement ratios of ~10 and 30%, respectively, for each agent with acceptable tissue histology. Mini-tablets of uC11 and FD4 however delivered more FD4 compared to C10-FD-4 mini-tablets in both regions, as reflected by a statistically higher AUC, and with no evidence of membrane perturbation. The unsaturated bond in uC11 therefore confers a reduction in lipophilicity and cytotoxicity compared to C11, and the resulting permeation enhancement is on a par with or superior to that of C10, a key component of formulations in current phase II oral peptide clinical trials.

KEY WORDS

10-undecylenic acid Caco-2 cells intestinal permeation enhancement medium chain fatty acids oral peptides 

Notes

ACKNOWLEDGMENTS

This work was co-funded by Science Foundation Ireland Strategic Research Cluster grant 07/SRC/B1154 and an industry partnership award to EW from the Irish Research Council with sponsorship from Merrion Pharmaceuticals, Ireland. We thank Margaret Coady for assistance with histopathology.

Supplementary material

12248_2014_9634_MOESM1_ESM.doc (29 kb)
Suppl. Table 1 (DOC 29 kb)

REFERENCES

  1. 1.
    Pinto-Reis C, Silva C, Martinho N, Rosado C. Drug carriers for oral delivery of peptides and proteins: accomplishments and future perspectives. Ther Deliv. 2013;4:251–65.PubMedCrossRefGoogle Scholar
  2. 2.
    Maher S, Brayden DJ. Overcoming poor permeability: translating intestinal permeation enhancers for oral peptide delivery. Drug Discov Today Technol. 2012;9:e113–9.CrossRefGoogle Scholar
  3. 3.
    Aungst BJ. Intestinal permeation enhancers. AAPS J. 2012;14:10–8.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Binkley N, Bolognese M, Sidorowicz-Bialynicka A, Vally T, Trout R, Miller C, et al. A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: the oral calcitonin in postmenopausal osteoporosis (ORACAL) trial. J Bone Miner Res. 2012;27:1821–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Tuvia S, Atsmon J, Teichman SL, Katz S, Salama P, Pelled D, et al. Oral octreotide absorption in human subjects: comparable pharmacokinetics to parenteral octreotide and effective growth hormone suppression. J Clin Endocrinol Metab. 2012;97:2362–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Walsh E, Adamczyk B, Chalasani KB, Maher M, O’Toole EB, Fox J, et al. Oral delivery of macromolecules: rationale underpinning Gastrointestinal Permeation Enhancement Technology (GIPET®). Ther Deliv. 2011;2:1595–610.PubMedCrossRefGoogle Scholar
  7. 7.
    Krug SM, Amasheh M, Dittman I, Christoffel I, Fromm M, Amasheh S. Sodium caprate as enhancer of macromolecule permeation across tricellular tight junctions of intestinal cells. Biomaterials. 2013;34:275–82.PubMedCrossRefGoogle Scholar
  8. 8.
    Maher S, Leonard TW, Jacobsen J, Brayden DJ. Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic. Adv Drug Deliv Rev. 2009;61:1427–49.PubMedCrossRefGoogle Scholar
  9. 9.
    Wang X, Maher S, Brayden DJ. Restoration of rat colonic epithelium after in situ intestinal instillation of the absorption promoter, sodium caprate. Ther Deliv. 2010;1:75–82.PubMedCrossRefGoogle Scholar
  10. 10.
    Mclain N, Ascanio R, Baker C, Strohaver RA, Dolan JW. Undecylenic acid inhibits morphogenesis of Candida albicans. Antimicrob Agents Chemother. 2000;44:2873–5.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Gonçalves LM, Del Bel Cury AA, Sartoratto A, Garcia Rehder VL, Silva WJ. Effects of undecylenic acid released from denture liner on Candida biofilms. J Dent Res. 2012;91:985–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Helms S, Miller A. Natural treatment of chronic rhinosinusitis. Altern Med Rev. 2006;11:196–207.PubMedGoogle Scholar
  13. 13.
    Undecylenic acid. Monograph Altern Med Rev. 2002; 7:68–70. http://www.altmedrev.com/publications/7/1/68.pdf. Accessed 16 June 2014.
  14. 14.
  15. 15.
    Helenius A, Simons K. Solubilization of membranes by detergents. Biochim Biophys Acta Rev Biomembr. 1975;415:29–79.CrossRefGoogle Scholar
  16. 16.
    Lichtenberg D, Robson RJ, Dennis EA. Solubilization of phospholipids by detergents structural and kinetic aspects. Biochim Biophys Acta. 1983;737:285–304.PubMedCrossRefGoogle Scholar
  17. 17.
    Aungst BJ, Rogers NJ, Shefter E. Enhancement of naloxone penetration through human skin in vitro using fatty acids, fatty alcohols, surfactants, sulphoxides and amides. Int J Pharm. 1986;33:225–34.CrossRefGoogle Scholar
  18. 18.
    US2012/0269881(A9) (Noven Pharmaceuticals Inc. USA). Trandermal drug delivery device including an occlusive backing.Google Scholar
  19. 19.
    Muchow M, Maincent P, Müller RH, Keck CM. Production and characterization of testosterone undecanoate-loaded NLC for oral bioavailability enhancement. Drug Dev Ind Pharm. 2011;37:8–14.PubMedCrossRefGoogle Scholar
  20. 20.
    Yin AY, Htun M, Swerdloff RS, Diaz-Arjonilla M, Dudley RE, Faulkner S, et al. Reexamination of pharmacokinetics of oral testosterone undecanoate in hypogonadal men with a new self-emulsifying formulation. J Androl. 2012;33:190–201.PubMedCrossRefGoogle Scholar
  21. 21.
    Hickey S, Hagan SA, Kudryashov E, Buckin V. Analysis of phase diagram and microstructural transitions in an ethyl oleate/water/Tween 80/Span 20 microemulsion system using high-resolution ultrasonic spectroscopy. Int J Pharm. 2010;388:213–22.PubMedCrossRefGoogle Scholar
  22. 22.
    Hubatsch I, Ragnarsson EG, Artursson P. Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nat Protoc. 2007;2:2111–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Whitehead K, Mitragotri S. Mechanistic analysis of chemical permeation enhancers for oral drug delivery. Pharm Res. 2008;25:1412–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Anderberg EK, Nyström C, Artursson P. Epithelial transport of drugs in cell culture. VII: effects of pharmaceutical surfactant excipients and bile acids on transepithelial permeability in monolayers of human intestinal epithelial (Caco-2) cells. J Pharm Sci. 1992;81:879–87.PubMedCrossRefGoogle Scholar
  25. 25.
    O’Brien PJ, Irwin W, Diaz D, Howard-Cofield E, Krejsa CM, Slaughter MR, et al. High concordance of drug-induced human hepatotoxicity with in vitro cytotoxicity measured in a novel cell-based model using high content screening. Arch Toxicol. 2006;80:580–604.PubMedCrossRefGoogle Scholar
  26. 26.
    Rawlinson LA, O’Brien PJ, Brayden DJ. High content analysis of cytotoxic effects of pDMAEMA on human intestinal epithelial and monocyte cultures. J Control Release. 2010;146:84–92.PubMedCrossRefGoogle Scholar
  27. 27.
    Bzik VA, Medani M, Baird AW, Winter DC, Brayden DJ. Mechanisms of action of zinc on rat intestinal epithelial electrogenic ion secretion: insights into its antidiarrhoeal actions. J Pharm Pharmacol. 2012;64:644–53.PubMedCrossRefGoogle Scholar
  28. 28.
    Ungell AL, Nylander S, Bergstrand S, Sjöberg Å, Lennernäs H. Membrane transport of drugs in different regions of the intestinal tract of the rat. J Pharm Sci. 1998;87:360–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Lindmark T, Schipper N, Lazorová L, De Boer AG, Artursson P. Absorption enhancement in intestinal epithelial Caco-2 monolayers by sodium caprate: assessment of molecular weight dependence and demonstration of transport toutes. J Drug Target. 1998;5:215–23.PubMedCrossRefGoogle Scholar
  30. 30.
    Maroni A, Zema L, Del Curto MD, Foppoli A, Gazzaniga A. Oral colon delivery of insulin with the aid of functional adjuvants. Adv Drug Deliv Rev. 2012;64:540–56.PubMedCrossRefGoogle Scholar
  31. 31.
    Uchiyama T, Sugiyama T, Quan YS, Kotani A, Okada N, Fujita T, et al. Enhanced permeability of insulin across the rat intestinal membrane by various absorption enhancers: the intestinal mucosal toxicity and absorption-enhancing mechanism of n-lauryl-β-d-maltopyranoside. J Pharm Pharmacol. 1999;51:1241–50.PubMedCrossRefGoogle Scholar
  32. 32.
    Tomita M, Sawada T, Ogawa T, Ouchi H, Hayashi M, Awazu S. Differences in the enhancing effects of sodium caprate on colonic and jejunal drug absorption. Pharm Res. 1992;9:648–53.PubMedCrossRefGoogle Scholar
  33. 33.
    Petersen SB, Nolan G, Maher S, Rahbek UL, Guldbrandt M, Brayden DJ. Evaluation of alkylmaltosides as intestinal permeation enhancers: comparison between rat intestinal mucosal sheets and Caco-2 monolayers. Eur J Pharm Sci. 2012;47:701–12.PubMedCrossRefGoogle Scholar
  34. 34.
    Brayden DJ, Mrsny R. Oral peptide delivery: prioritizing the leading technologies. Ther Deliv. 2011;2:1567–73.PubMedCrossRefGoogle Scholar
  35. 35.
    Cox A, Rawlinson LA, Baird A, Bzik V, Brayden D. In vitro interactions between the oral absorption promoter, sodium caprate (C10) and S. typhimurium in rat intestinal ileal mucosae. Pharm Res. 2008;25:114–22.PubMedCrossRefGoogle Scholar
  36. 36.
    Kararli TT. Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals. Biopharm Drug Dispos. 1995;16:351–80.PubMedCrossRefGoogle Scholar
  37. 37.
    Lindmark T, Söderholm J, Olaison G, Alván G, Ocklind G, Artursson P. Mechanism of absorption enhancement in humans after rectal administration of ampicillin in suppositories containing sodium caprate. Pharm Res. 1997;14:930–5.PubMedCrossRefGoogle Scholar
  38. 38.
    Cano-Cebrián MJ, Zornoza T, Granero L, Polache P. Intestinal absorption enhancement via the paracellular route by fatty acids, chitosans and others: a target for drug delivery. Curr Drug Deliv. 2005;2:9–22.PubMedCrossRefGoogle Scholar
  39. 39.
    Swenson ES, Milisen W, Curatolo W. Intestinal permeability enhancement: efficacy, acute local toxicity, and reversibility. Pharm Res. 1994;11:1132–42.PubMedCrossRefGoogle Scholar
  40. 40.
    Fan D, Wu X, Dong W, Sun W, Li J, Tang X. Enhancement by sodium caprate and sodium deoxycholate of the gastrointestinal absorption of berberine chloride in rats. Drug Dev Industrial Pharmacy. 2013;39:1447–56.CrossRefGoogle Scholar
  41. 41.
    Leclercq S, Cani PD, Neyrinck AM, Stärkel P, Jamar F, Mikolajczak M, et al. Role of intestinal permeability and inflammation in the biological and behavioral control of alcohol-dependent subjects. Brain Behav Immun. 2012;26:911–8.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  1. 1.School of Veterinary Medicine, Veterinary Sciences Centre and Conway InstituteUniversity College DublinDublin 4Ireland

Personalised recommendations