Abstract
In vitro and in vivo skin penetration of three drugs with different lipophilicities and the enhancing effects of l-geranylazacycloheptan-2-one (GACH) were studied in rats. In vivo drug absorption profiles obtained by deconvolution of urinary excretion profiles were compared to the corresponding in vitro data obtained with a diffusion experiment. In vivo skin penetration of lipophilic butylparaben was considerably greater than that observed in vitro, while hydrophilic mannitol and acyclovir showed low penetration in both systems without GACH pretreatment. On the other hand, GACH enhanced mannitol and acyclovir penetration, especially in the in vivo system. Analysis of absorption profiles, using a two-layer skin model with polar and nonpolar routes in the stratum corneum, suggested that the diffusion length of a viable layer (viable epidermis and dermis) was shorter in vivo than in vitro and the effective area of the polar route in the stratum corneum was larger in vitro without GACH pretreatment. GACH increased the partitioning of acyclovir into the nonpolar route to the same extent in both systems. In addition, GACH increased the effective area of the polar route in vivo, probably because of enhanced water permeability; however, this effect was smaller in vitro since the stratum corneum was already hydrated even without GACH pretreatment.
Similar content being viewed by others
REFERENCES
R. J. Sheuplein and I. H. Blank. Permeability of the skin. Physiol. Rev. 51:702–747 (1971).
AH. Ghanem, H. Mahmoud, W. I. Higuchi, U. D. Rohr, S. Borsadia, P. Liu, J. L. Fox, and W. R. Good. The effects of ethanol on the transport of β-estradiol and other permeants in hairless mouse skin. II. A new quantitative approach. J. Control. Release 6:75–83 (1987).
K. Tojo, C. C. Chiang, and Y. W. Chien. Drug permeation across the skin: Effect of penetrant hydrophilicity. J. Pharm. Sci. 76:123–126 (1987).
H. Okamoto, F. Yamashita, K. Saito, and M. Hashida. Analysis of drug penetration through the skin by the two-layer skin model. Pharm. Res. 6:931–937 (1989).
C. D. Yu, J. L. Fox, N. F. H. Ho, and W. I. Higuchi. Physical model evaluation of topical prodrug delivery—Simultaneous transport and bioconversion of vidarabine-5′-valerate II. Parameter determination. J. Pharm. Sci. 68:1347–1357 (1979).
K. H. Valia, K. Tojo, and Y. W. Chien. Long-term permeation kinetics of estradiol: (III) kinetic analyses of the simultaneous skin permeation and bioconversion of estradiol esters. Drug Dev. Ind. Pharm. 11:1133–1173 (1985).
R. H. Guy, J. Hadgraft, and H. I. Maibach. A pharmacokinetic model for percutaneous absorption. Int. J. Pharm. 11:119–129 (1982).
S. K. Chandrasekaran, W. Bayne, and J. E. Shaw. Pharmacokinetics of drug permeation through human skin. J. Pharm. Sci. 67:1370–1374 (1978).
K. Tojo. Concentration profile in plasma after transdermal drug delivery. Int. J. Pharm. 43:201–205 (1988).
K. Sato, T. Oda, K. Sugibayashi, and Y. Morimoto. Estimation of blood concentration of drugs after topical application from in vitro skin permeation data. II. Approach by using diffusion model and compartment model. Chem. Pharm. Bull. 36:2624–2632 (1988).
K. Sato, T. Oda, K. Sugibayashi, and Y. Morimoto. Estimation of blood concentration of drugs after topical application from in vitro skin permeation data. I. Prediction by convolution and confirmation by deconvolution. Chem. Pharm. Bull. 36:2232–2238 (1988).
T. J. Franz, Percutaneous absorption. On the relevance of in vitro data. J. Invest. Dermatol. 64:190–195 (1975).
R. L. Bronaugh, R. F. Stewart, E. R. Congdon, and A. L. Giles, Jr. Methods for in vitro percutaneous absorption studies I. Comparison with in vitro results. Toxicol. Appl. Pharmacol. 62:474–480 (1982).
R. L. Bronaugh and H. I. Maibach. Percutaneous absorption of nitroaromatic compounds: In vivo and in vitro studies in the human and monkey. J. Invest. Dermatol. 84:180–183 (1985).
R. L. Bronaugh and T. J. Franz. Vehicle effects on percutaneous absorption: In vivo and in vitro comparisons with human skin. Br. J. Dermatol. 115:1–11 (1986).
H. Okamoto, M. Ohyabu, M. Hashida, and H. Sezaki. Enhanced penetration of mitomycin C through hairless mouse and rat skin by enhancers with terpene moieties. J. Pharm. Pharmacol. 39:531–534 (1986).
H. Okamoto, M. Hashida, and H. Sezaki. Structure-activity relationship of 1-alkyl-or 1-alkenylazacycloalkanone derivatives as percutaneous penetration enhancers. J. Pharm. Sci. 77:418–424 (1988).
H. Okamoto, K. Muta, M. Hashida, and H. Sezaki. Percutaneous penetration of acyclovir through excised hairless mouse and rat skin: Effect of vehicle and percutaneous penetration enhancer. Pharm. Res. 7:64–68 (1990).
H. Okamoto, M. Hashida, and H. Sezaki. Effect of 1-alkyl-or 1-alkenylazacycloalkanone derivatives on the penetration of drugs with different lipophilicities in guinea pig skin. J. Pharm. Sci. 80:39–45 (1991).
F. Yamashita, T. Yoshioka, Y. Koyama, H. Okamoto, H. Sezaki, and M. Hashida. Analysis of skin penetration enhancement based on a two-layer skin diffusion model with polar and nonpolar routes in the stratum corneum: Dose-dependent effect of 1-geranylazacycloheptan-2-one on drugs with different lipophilicities. Biol. Pharm. Bull. 16:690–697 (1993).
F. Yamashita, Y. Koyama, H. Sezaki, and M. Hashida. Estimation of a concentration profile of acyclovir in the skin after topical administration. Int. J. Pharm. 89:199–206 (1993).
H. Kiwada, K. Morita, M. Hayashi, S. Awazu, and M. Hanano. A new numerical calculation method for deconvolution in linear compartment analysis of pharmacokinetics. Chem. Pharm. Bull. 25:1312–1318 (1977).
R. T. Tregear. Physical Functions of Skin, Academic Press, New York, 1966, pp. 1–52.
Y. Yano, K. Yamaoka, and H. Tanaka. A nonlinear least square program, MULTI(FILT), based on fast inverse Laplace transform for microcomputers. Chem. Pharm. Bull. 37:1035–1038 (1989).
C. Ackermann and G. L. Flynn. Ether-water partitioning and permeability through nude mouse skin in vitro. I. Urea, thiourea, glycerol and glucose. Int. J. Pharm. 36:61–66 (1987).
C. Ackermann, G. L. Flynn, and W. M. Smith. Ether-water partitioning and permeability through nude mouse skin in vitro. II. Hydrocortisone 21-n-alkyl esters, alkanols and hydrophilic compounds. Int. J. Pharm. 36:67–71 (1987).
R. L. Bronaugh and R. F. Stewart. Methods for in vitro percutaneous absorption studies. VI. Preparation of the barrier layer. J. Pharm. Sci. 75:487–491 (1986).
B. Idson. Percutaneous absorption. J. Pharm. Sci. 64:901–924 (1975).
W. J. Lambert, W. I. Higuchi, K. Knutson, and S. L. Krill. Effects of long-term hydration leading to the development of polar channels in hairless mouse stratum corneum. J. Pharm. Sci. 78:925–928 (1989).
P. G. Green, R. H. Guy, and J. Hadgraft. In vitro and in vivo enhancement of skin permeation with oleic and lauric acids. Int. J. Pharm. 48:103–111 (1988).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Yamashita, F., Bando, H., Koyama, Y. et al. In Vivo and in Vitro Analysis of Skin Penetration Enhancement Based on a Two-Layer Diffusion Model with Polar and Nonpolar Routes in the Stratum Corneum. Pharm Res 11, 185–191 (1994). https://doi.org/10.1023/A:1018986803958
Issue Date:
DOI: https://doi.org/10.1023/A:1018986803958