Abstract
Purpose
The present study evaluated the effects of fatty acids commonly present in cosmetic and topical formulations on permeation enhancement across human epidermal membrane (HEM) lipoidal pathway when the fatty acids saturated the SC lipid domain without cosolvents (Emax).
Methods
HEM was treated with neat fatty acids or fatty acid suspensions to determine Emax. A volatile solvent system was used to deposit fatty acids on HEM surface to compare fatty acid enhancer efficiency in topical volatile formulations with Emax. To elucidate permeation enhancement mechanism(s), estradiol (E2β) uptake into fatty acid-treated SC lipid domain was determined.
Results
Emax of fatty acids was shown to increase with their octanol solubilities and decrease with their lipophilicities, similar to our previous findings with other enhancers. Emax of solid fatty acids was shown to depend on their melting points, an important parameter to the effectiveness of the enhancers. The E2β uptake results suggest that enhancer-induced permeation enhancement across HEM is related to enhanced permeant partitioning into the SC lipid domain.
Conclusions
The results suggest Emax as a model for studying the permeation enhancement effect of the fatty acids and their structure enhancement relationship.
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REFERENCES
Al-Qallaf B, Das DB, Mori D, Cui Z. Modelling transdermal delivery of high molecular weight drugs from microneedle systems. Philosophical Transactions of the Royal Society a-Mathematical Physical and Engineering Sciences. 2007;365:2951–67.
Karande P, Jain A, Ergun K, Kispersky V, Mitragotri S. Design principles of chemical penetration enhancers for transdermal drug delivery. Proc Natl Acad Sci U S A. 2005;102:4688–93.
Ansel HC, Allen LV, Popovich NG. Pharmaceutical dosage forms and drug delivery systems. Philadelphia: Lippincott-Williams & Wilkins; 1999.
El-Gibaly I, Mohamed FA, Shehata M. Effect of some penetration enhancers on release of clotrimazole from different gel formulations and histological changes of rabbit skin. Pharmazeutische Industrie. 1998;60:1088–95.
Finnin BC, Morgan TM. Transdermal penetration enhancers: applications, limitations, and potential. J Pharm Sci. 1999;88:955–8.
Chantasart D, Sa-Nguandeekul P, Prakongpan S, Li SK, Higuchi WI. Comparison of the effects of chemical permeation enhancers on the lipoidal pathways of human epidermal membrane and hairless mouse skin and the mechanism of enhancer action. J Pharm Sci. 2007;96:2310–26.
Ogiso T, Paku T, Iwaki M, Tanino T. Percutaneous penetration of fluorescein isothiocyanate-dextrans and the mechanism for enhancement effect of enhancers on the intercellular penetration. Biol Pharm Bull. 1995;18:1566–71.
Goates CY, Knutson K. Enhanced permeation and stratum corneum structural alterations in the presence of dithiothreitol. Biochim Biophys Acta. 1993;1153:289–98.
Niazy EM. Influence of oleic-acid and other permeation promoters on transdermal delivery of dihydroergotamine through rabbit skin. Int J Pharm. 1991;67:97–100.
Chantasart D, Li SK, He N, Warner KS, Prakongpan S, Higuchi WI. Mechanistic studies of branched-chain alkanols as skin permeation enhancers. J Pharm Sci. 2004;93:762–79.
Ibrahim SA, Li SK. Effects of chemical enhancers on human epidermal membrane: Structure-enhancement relationship based on maximum enhancement Emax. J Pharm Sci. 2009;98:926–44.
Karande P, Jain A, Mitragotri S. Insights into synergistic interactions in binary mixtures of chemical permeation enhancers for transdermal drug delivery. J Control Release. 2006;115:85–93.
Morgan TM, Parr RA, Reed BL, Finnin BC. Enhanced transdermal delivery of sex hormones in swine with a novel topical aerosol. J Pharm Sci. 1998;87:1219–25.
Ibrahim SA, Li SK. Effects of solvent deposited enhancers on transdermal permeation and their relationship with Emax. J Control Release. 2009;136:117–24.
Cooper ER. Increased skin permeability for lipophilic molecules. J Pharm Sci. 1984;73:1153–6.
Barry BW, Bennett SL. Effect of penetration enhancers on the permeation of mannitol, hydrocortisone and progesterone through human skin. J Pharm Pharmacol. 1987;39:535–46.
Kandimalla K, Kanikkannan N, Andega S, Singh M. Effect of fatty acids on the permeation of melatonin across rat and pig skin in-vitro and on the transepidermal water loss in rats in-vivo. J Pharm Pharmacol. 1999;51:783–90.
Aungst BJ. Structure/effect studies of fatty acid isomers as skin penetration enhancers and skin irritants. Pharm Res. 1989;6:244–7.
Aungst BJ, Rogers NJ, Shefter E. Enhancement of naloxone penetration through human skin in vitro using fatty-acids, fatty alcohols, surfactants. sulfoxides and amides. Int J Pharm. 1986;33:225–34.
Ongpipattanakul B, Burnette RR, Potts RO, Francoeur ML. Evidence that oleic acid exists in a separate phase within stratum corneum lipids. Pharm Res. 1991;8:350–4.
Nanayakkara GR, Bartlett A, Forbes B, Marriott C, Whitfield PJ, Brown MB. The effect of unsaturated fatty acids in benzyl alcohol on the percutaneous permeation of three model penetrants. Int J Pharm. 2005;301:129–39.
Yokomizo Y, Sagitani H. The effects of phospholipids on the percutaneous penetration of indomethacin through the dorsal skin of guinea pig in vitro. 2. The effects of the hydrophobic group in phospholipids and a comparison with general enhancers. J Control Release. 1996;42:37–46.
Kasting GB, Bowman LA. Electrical analysis of fresh, excised human skin: a comparison with frozen skin. Pharm Res. 1990;7:1141–6.
Warner KS, Li SK, He N, Suhonen TM, Chantasart D, Bolikal D, Higuchi WI. Structure-activity relationship for chemical skin permeation enhancers: probing the chemical microenvironment of the site of action. J Pharm Sci. 2003;92:1305–22.
S.A. Ibrahim and S.K. Li. Chemical enhancer solubility in human stratum corneum lipids and enhancer mechanism of action on stratum corneum lipid domain. Int J Pharm. In Press (2009).
S.H. Yalkowsky and R.M. Dannenfelser. Aquasol Database of Aqueous Solubility., Version 5, 1992.
Nair VB, Panchagnula R. Effect of iontophoresis and fatty acids on permeation of arginine vasopressin through rat skin. Pharmacol Res. 2003;47:563–9.
ACKNOWLEDGMENTS
This research was supported in part by NIH Grant GM 063559. The authors thank Dr. Jinsong Hao for her help in the laboratory.
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Ibrahim, S.A., Li, S.K. Efficiency of Fatty Acids as Chemical Penetration Enhancers: Mechanisms and Structure Enhancement Relationship. Pharm Res 27, 115–125 (2010). https://doi.org/10.1007/s11095-009-9985-0
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DOI: https://doi.org/10.1007/s11095-009-9985-0