Oleic acid and oleyl alcohol are commonly used permeation and penetration enhancers to facilitate topical drug delivery. Here, we aimed to better understand the mechanism of their enhancing effects in terms of their interactions with the human skin barrier using diclofenac diethylamine (DIC-DEA), a nonsteroidal anti-inflammatory drug for topical pain management. Oleic acid promoted DIC-DEA permeation through ex vivo human skin more rapidly than oleyl alcohol (both applied at 0.75%) due to fluidization of stratum corneum lipids as revealed by infrared spectroscopy. After 12 h, the effect of these enhancers on DIC-DEA permeation leveled off, fluidization was no longer evident, and skin permeabilization was mainly due to the formation of fluid enhancer-rich domains. Contrary to oleyl alcohol, oleic acid adversely affected two indicators of the skin barrier integrity, transepidermal water loss and skin electrical impedance. The content of oleyl alcohol in the stratum corneum was lower than that of oleic acid (even 12 h after the enhancers were removed from the skin surface), but it caused higher DIC-DEA retention in both epidermis and dermis compared to oleic acid. The effects of oleyl alcohol and oleic acid on DIC-DEA permeation and retention in the skin were similar after a single and repeated application (4 doses every 12 h). Thus, oleyl alcohol offers several advantages over oleic acid for topical drug delivery.

HALEON CH SARL Route de l'Etraz 2 Case Postale 1279 Nyon 1260 Switzerland

Skin Barrier Research Group Charles University Faculty of Pharmacy in Hradec Králové Akademika Heyrovského 1203 50005 Hradec Králové Czech Republic

Zobrazit více v PubMed

Williams A.Transdermal and Dermal Drug Delivery: From Theory to Clinical Practice; Pharmaceutical Press: London, 2003. 0-85369-489-3.

Derry S.; Moore R. A.; Gaskell H.; McIntyre M.; Wiffen P. J.. Topical NSAIDs for acute musculoskeletal pain in adults Cochrane Database Syst. Rev. 2015. (6), CD007402.10.1002/14651858.CD007402.pub3. PubMed DOI PMC

Panwar A.; Upadhyay N.; Bairagi M.; Gujar S.; Darwhekar G.; Jain D. Emulgel: A review. Asian J. Pharm. Life Sci. 2011, 2231, 4423.

Hagen M.; Baker M. Skin penetration and tissue permeation after topical administration of diclofenac. Curr. Med. Res. Opin. 2017, 33 (9), 1623–1634. 10.1080/03007995.2017.1352497. PubMed DOI

Pradal J.; Vallet C. M.; Frappin G.; Bariguian F.; Lombardi M. S. Importance of the formulation in the skin delivery of topical diclofenac: not all topical diclofenac formulations are the same. J. Pain Res. 2019, 1149–1154. 10.2147/JPR.S191300. PubMed DOI PMC

Pradal J.; Vallet C.; Frappin F.; Lombardi M. S.; Cheignon C. Topical delivery of NSAIDs: influence of drug choice, formulation, and dose on in vitro skin permeation. Postgrad Med 2018, 130, 59.

Kováčik A.; Kopecna M.; Vavrova K. Permeation enhancers in transdermal drug delivery: benefits and limitations. Expert Opin. Drug Delivery 2020, 17 (2), 145–155. 10.1080/17425247.2020.1713087. PubMed DOI

Marjukka Suhonen T.; Bouwstra J. A.; Urtti A. Chemical enhancement of percutaneous absorption in relation to stratum corneum structural alterations. J. Controlled Release 1999, 59 (2), 149–161. 10.1016/s0168-3659(98)00187-4. PubMed DOI

Williams A. C.; Barry B. W. Penetration enhancers. Adv. Drug Deliver Rev. 2012, 64, 128–137. 10.1016/j.addr.2012.09.032. PubMed DOI

Mao G.; VanWyck D.; Xiao X.; Mack Correa M. C.; Gunn E.; Flach C. R.; Mendelsohn R.; Walters R. M. Oleic acid disorders stratum corneum lipids in Langmuir monolayers. Langmuir 2013, 29 (15), 4857–4865. 10.1021/la4002384. PubMed DOI

Rowat A. C.; Kitson N.; Thewalt J. L. Interactions of oleic acid and model stratum corneum membranes as seen by 2H NMR. Int. J. Pharm. 2006, 307 (2), 225–231. 10.1016/j.ijpharm.2005.10.008. PubMed DOI

Naik A.; Pechtold L. A. R. M.; Potts R. O.; Guy R. H. Mechanism of oleic acid-induced skin penetration enhancement in vivo in humans. J. Controlled Release 1995, 37 (3), 299–306. 10.1016/0168-3659(95)00088-7. DOI

Ongpipattanakul B.; Burnette R. R.; Potts R. O.; Francoeur M. L. Evidence that oleic acid exists in a separate phase within stratum corneum lipids. Pharm. Res. 1991, 8 (3), 350–354. 10.1023/a:1015845632280. PubMed DOI

Mak V. H.; Potts R. O.; Guy R. H. Oleic acid concentration and effect in human stratum corneum: non-invasive determination by attenuated total reflectance infrared spectroscopy in vivo. J. Controlled Release 1990, 12 (1), 67–75. 10.1016/0168-3659(90)90184-U. DOI

Francoeur M. L.; Golden G. M.; Potts R. O. Oleic acid: its effects on stratum corneum in relation to (trans)dermal drug delivery. Pharm. Res. 1990, 7 (6), 621–627. 10.1023/a:1015822312426. PubMed DOI

Tanojo H.; Boelsma E.; Junginger H. E.; Ponec M.; Bodde H. E. In vivo human skin permeability enhancement by oleic acid: a laser Doppler velocimetry study. J. Controlled Release 1999, 58 (1), 97–104. 10.1016/S0168-3659(98)00144-8. PubMed DOI

Andega S.; Kanikkannan N.; Singh M. Comparison of the effect of fatty alcohols on the permeation of melatonin between porcine and human skin. J. Controlled Release 2001, 77 (1–2), 17–25. 10.1016/S0168-3659(01)00439-4. PubMed DOI

Dias M.; Naik A.; Guy R. H.; Hadgraft J.; Lane M. E. In vivo infrared spectroscopy studies of alkanol effects on human skin. Eur. J. Pharm. Biopharm 2008, 69 (3), 1171–1175. 10.1016/j.ejpb.2008.02.006. PubMed DOI

Kim M. J.; Doh H. J.; Choi M. K.; Chung S. J.; Shim C. K.; Kim D. D.; Kim J. S.; Yong C. S.; Choi H. G. Skin permeation enhancement of diclofenac by fatty acids. Drug Delivery 2008, 15 (6), 373–379. 10.1080/10717540802006898. PubMed DOI

Zhang Q.; Saad P.; Mao G.; Walters R. M.; Mack Correa M. C.; Mendelsohn R.; Flach C. R. Infrared Spectroscopic Imaging Tracks Lateral Distribution in Human Stratum Corneum. Pharm. Res. 2014, 31 (10), 2762–2773. 10.1007/s11095-014-1373-8. PubMed DOI

Ibrahim S. A.; Li S. K. Chemical enhancer solubility in human stratum corneum lipids and enhancer mechanism of action on stratum corneum lipid domain. Int. J. Pharm. 2010, 383 (1–2), 89–98. 10.1016/j.ijpharm.2009.09.014. PubMed DOI PMC

Boelsma E.; Tanojo H.; Boddé H.; Ponec M. Assessment of the potential irritancy of oleic acid on human skin: evaluation in vitro and in vivo. Toxicol. In Vitro 1996, 10 (6), 729–742. 10.1016/S0887-2333(96)00053-7. PubMed DOI

Lashmar U. T.; Hadgraft J.; Thomas N. Topical application of penetration enhancers to the skin of nude mice: a histopathological study. J. Pharm. Pharmacol. 2011, 41 (2), 118–122. 10.1111/j.2042-7158.1989.tb06405.x. PubMed DOI

Public Assessment Report DE/H/5493 + 6245 + 6603/001–002/DC for Diclofenac AbZ Schmerzgel Diclox/Diclox forte Diclofenac-ratiopharm 2020https://mri.cts-mrp.eu/Human/Downloads/DE_H_5493_002_PAR.pdf.

Kienzler J. L.; Gold M.; Nollevaux F. Systemic bioavailability of topical diclofenac sodium gel 1% versus oral diclofenac sodium in healthy volunteers. J. Clin. Pharmacol. 2010, 50 (1), 50–61. 10.1177/0091270009336234. PubMed DOI

Sioufi A.; Pommier F.; Boschet F.; Godbillon J.; Lavoignat D.; Salliere D. Percutaneous absorption of diclofenac in healthy volunteers after single and repeated topical application of diclofenac Emulgel. Biopharm. Drug Dispos. 1994, 15 (6), 441–449. 10.1002/bdd.2510150602. PubMed DOI

Zhang Q.; Flach C. R.; Mendelsohn R.; Page L.; Whitson S.; Boncheva Bettex M. Visualization of Epidermal Reservoir Formation from Topical Diclofenac Gels by Raman Spectroscopy. J. Pain Res. 2020, 13, 1621–1627. 10.2147/JPR.S253069. PubMed DOI PMC

Kopečná M.; Kovacik A.; Novak P.; Boncheva Bettex M.; Vavrova K. Transdermal Permeation and Skin Retention of Diclofenac and Etofenamate/Flufenamic Acid From Over-the-Counter Pain Relief Products. J. Pharm. Sci. 2021, 110 (6), 2517–2523. 10.1016/j.xphs.2021.01.022. PubMed DOI

Fasano W. J.; Hinderliter P. M. The Tinsley LCR Databridge Model 6401 and electrical impedance measurements to evaluate skin integrity in vitro. Toxicol. In Vitro 2004, 18 (5), 725–729. 10.1016/j.tiv.2004.01.003. PubMed DOI

Kopečná M.; Machacek M.; Prchalova E.; Stepanek P.; Drasar P.; Kotora M.; Vavrova K. Galactosyl Pentadecene Reversibly Enhances Transdermal and Topical Drug Delivery. Pharm. Res. 2017, 34 (10), 2097–2108. 10.1007/s11095-017-2214-3. PubMed DOI

Kopečná M.; Macháček M.; Nováčková A.; Paraskevopoulos G.; Roh J.; Vávrová K. Esters of terpene alcohols as highly potent, reversible, and low toxic skin penetration enhancers. Sci. Rep 2019, 9 (1), 1461710.1038/s41598-019-51226-5. PubMed DOI PMC

Roberts M. S.; Cross S. E. A physiological pharmacokinetic model for solute disposition in tissues below a topical below a topical application site. Pharm. Res. 1999, 16 (9), 1392–1398. 10.1023/A:1018998908655. PubMed DOI

Kienzler J. L.; Gold M.; Nollevaux F. Systemic bioavailability of topical diclofenac sodium gel 1% versus oral diclofenac sodium in healthy volunteers. J. Clin. Pharmacol. 2010, 50 (1), 50–61. 10.1177/0091270009336234. PubMed DOI

Sioufi A.; Pommier F.; Boschet F.; Godbillon J.; Lavoignat D.; Salliere D. Percutaneous absorption of diclofenac in healthy volunteers after single and repeated topical application of diclofenac Emulgel. Biopharm. Drug Dispos. 1994, 15 (6), 441–449. 10.1002/bdd.2510150602. PubMed DOI

Opálka L.; Kovacik A.; Sochorova M.; Roh J.; Kunes J.; Lenco J.; Vavrova K. Scalable Synthesis of Human Ultralong Chain Ceramides. Org. Lett. 2015, 17 (21), 5456–5459. 10.1021/acs.orglett.5b02816. PubMed DOI

Boncheva M.; Damien F.; Normand V. Molecular organization of the lipid matrix in intact Stratum corneum using ATR-FTIR spectroscopy. Biochim. Biophys. Acta, Biomembr. 2008, 1778 (5), 1344–1355. 10.1016/j.bbamem.2008.01.022. PubMed DOI