Transdermal Delivery of Highly Lipophilic Drugs: In Vitro Fluxes of Antiestrogens, Permeation Enhancers, and Solvents from Liquid Formulations
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Purpose. Highly lipophilic basic drugs, the antiestrogens AE 1 (log P = 5.82) and AE 2 (log P = 7.8) shall be delivered transdermally.
Methods. Transdermal permeation of drugs, enhancers, and solvents from various fluid formulations were characterized by in-vitro permeation studies through excised skin of hairless mice. Furthermore, differential scanning calorimetry (DSC) measurements of skin lipid phase transition temperatures were conducted.
Results. Transdermal flux of highly lipophilic drugs was extraordinarily enhanced by the unique permeation enhancer combination propylene glycol-lauric acid (9 + 1): steady-state fluxes of AE 1 and AE 2 were as high as 5.8 μg·cm−2·h−1 and 3.2 μg·cm−2·h−1, respectively. This dual enhancer formulation also resulted in a marked increase in the transdermal fluxes of the enhancers. Furthermore, skin lipid phase transition temperatures were significantly reduced by treatment with this formulation.
Conclusion. Transdermal delivery of highly lipophilic drugs can be realized by using the permeation enhancer combination propylene glycol-lauric acid. The extraordinary permeation enhancement for highly lipophilic drugs by this formulation is due to mutual permeation enhancement of these two enhancers and their synergistic lipid-fluidising activity in the stratum corneum.
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- 1.B. W. Barry. Dermatological formulations: Percutaneous absorption, Marcel Dekker, New York, 1983.Google Scholar
- 2.Y. W. Chien. Advances in transdermal systemic medication. In Y. W. Chien (ed.), Transdermal controlled systemic medications, Marcel Dekker, New York, 1987 pp. 1–24.Google Scholar
- 3.M. Dittgen. Transdermale Therapeutische Systeme. In R. H. Müller and G. E. Hildebrand (eds.), Pharmazeutische Technologie: Moderne Arzneiformen, Wiss. Verl. Ges., Stuttgart, 1997 pp. 81–104.Google Scholar
- 4.H. Schaefer and T. E. Redelmeier. Skin Barrier: Principles of percutaneous absorption, Karger, Basel, 1996.Google Scholar
- 5.R. S. Hinz, C. R. Lorence, C. D. Hodson, C. Hansch, L. L. Hall, and R. H. Guy. Percutaneous penetration of para-substituted phenols in vitro. Fundam.Appl.Toxicol. 17:575–583 (1991).Google Scholar
- 6.J. Hadgraft. Dermal and transdermal drug design. Int.J.Pharm.Med. 13:155–158 (1999).Google Scholar
- 7.A. Pardo, Y. Shiri, and S. Cohen. Percutaneous absorption of physostigmine: optimization of delivery from a binary solvent by thermodynamic control. J.Pharm.Sci. 79:573–578 (1990).Google Scholar
- 8.T. Ogiso and M. Shintani. Mechanism for the enhancement effect of fatty acids on the percutaneous absorption of propranolol. J.Pharm.Sci. 79:1065–1071 (1990).Google Scholar
- 9.B. J. Aungst, J. A. Blake, and M. A. Hussain. Contributions of drug solubilization, partitioning, barrier disruption, and solvent permeation to the enhancement of skin permeation of various compounds with fatty acids and amines. Pharm.Res. 7:712–718 (1990).Google Scholar
- 10.J. Hadgraft. Recent developments in topical and transdermal delivery. Eur.J.Drug.Metab.Pharmacokinet. 21:165–173 (1996).Google Scholar
- 11.S. Mitragotri, D. A. Edwards, D. Blankschtein, and R. Langer. A mechanistic study of ultrasonically-enhanced transdermal drug delivery. J.Pharm.Sci. 84:697–706 (1995).Google Scholar
- 12.S. J. Jiang, Y. K. Kim, and S. H. Lee. The ultrastructural changes of stratum corneum lipids after application of oleic acid in propylene glycol. Ann.Dermatol. 10:153–158 (1994).Google Scholar
- 13.H. Tanojo, J. A. Bouwstra, H. E. Junginger, and H. E. Boddé. In vitro human skin barrier modulation by fatty acids: skin permeation and thermal analysis studies. Pharm.Res. 14:42–49 (1997).Google Scholar
- 14.K. I. Cumming and A. J. Winfield. In vitro evaluation of a series of sodium carboxylates as dermal penetration enhancers. Int.J.Pharm. 108:141–148 (1994).Google Scholar
- 15.S. Kitagawa, A. Hosokai, Y. Kaseda, N. Yamamoto, Y. Kaneko, and E. Matsuoka. Permeability of benzoic acid derivatives in excised guinea pig dorsal skin and effects of L-menthol. Int.J.Pharm. 161:115–122 (1998).Google Scholar
- 16.P. A. Cornwell, B. W. Barry, J. A. Bouwstra, and G. S. Gooris. Modes of action of terpene penetration enhancers in human skin; differential scanning calorimetry, small-angle X-ray diffraction and enhancer uptake studies. Int.J.Pharm. 127:9–26 (1996).Google Scholar
- 17.P. K. Wotton, B. Mollgaard, J. Hadgraft, and A. Hoelgaard. Vehicle effect on topical drug delivery; III: Effect of azone on the cutaneous permeation of metronidazole and propylene glycol. Int.J.Pharm. 24:19–26 (1985).Google Scholar
- 18.C. Günther. In vitro-und in vivo-Untersuchungen zur perkutanen Resorption von Estrogenen und Gestagenen als Grundlage für die Entwicklung eines transdermalen therapeutischen Systems. Ph. D. Thesis, Freie Universität, Berlin, 1990.Google Scholar
- 19.B. Bendas, U. Schmalfuß , and R. Neubert. Influence of propylene glycol as cosolvent on mechanisms of drug transport from hydrogels. Int.J.Pharm. 116:19–30 (1995).Google Scholar
- 20.R. L. Elder. (ed.) Cosmetic Ingredient Review Expert Panel: Final report on the safety assessment of oleic acid, lauric acid, palmitic acid, myristic acid and stearic acid. J.Am.Coll.Toxicol. 6:321–401 (1987).Google Scholar
- 21.F. A. Andersen. (ed.). Cosmetic Ingredient Review Expert Panel: Final report on the safety assessment of propylene glycol and polypropylene glycols. J.Am.Coll.Toxicol. 13:437–491 (1994).Google Scholar
- 22.S. Santoyo and P. Ygartua. Effect of skin pretreatment with fatty acids on percutaneous absorption and skin retention of piroxicam after ist topical application. Eur.J.Pharm.Biopharm. 50:245–250 (2000).Google Scholar
- 23.Y. Komata, A. Kaneko, and T. Fujie. Accumulation of lauric acid in skin as an enhancer for the percutaneous absorption of thiamine disulfide. Biol.Pharm.Bull. 18:791–793 (1995).Google Scholar
- 24.H.-J. Oh, Y.-K. Oh, and C.-K. Kim. Effects of vehicles and enhancers on transdermal delivery of melatonin. Int.J.Pharm. 212: 63–71 (2001).Google Scholar
- 25.P. W. Stott, A. C. Williams, and B. W. Barry. Mechanistic study into the enhanced transdermal permeation of a model β-blocker, propranolol, by fatty acids: a melting point depression effect. Int.J.Pharm. 219:161–176 (2001).Google Scholar
- 26.A. P. Funke. Transdermale Absorption von hoch lipophilen basischen Antiestrogenen aus Flüssigformulierungen und Matrix-Transdermalsystemen, Ph. D. Thesis, Freie Universität Berlin, 2000.Google Scholar
- 27.B. W. Barry. Lipid-protein-partitioning theory of skin penetration enhancement. J.Control.Release 15:237–248 (1991).Google Scholar
- 28.T. M. Suhonen, J. A. Bouwstra, and A. Urtti. Chemical enhancement of percutaneous absorption in relation to stratum corneum structural alterations. J.Control.Release 59:149–161 (1999).Google Scholar
- 29.C. S. Leopold and B. C. Lippold. An attempt to clarify the mechanism of the penetration enhancing effects of lipophilic vehicles with differential scanning calorimetry (DSC). J.Pharm.Pharmacol. 47:276–281 (1995).Google Scholar
- 30.Y. Takeuchi, H. Yasukawa, Y. Yamaoka, K. Taguchi, S. Fukushima, Y. Shimonaka, H. Nishinaga, and Y. Morimoto. Behavior of propylene glycol (PG) in dermis after treatment of rat intact skin surface with fatty acids, fatty amines or azone dissolved in PG. Biol.Pharm.Bull. 18:304–309 (1995).Google Scholar