Porcine Ear Skin as a Model for the Assessment of Transdermal Drug Delivery to Premature Neonates
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Purpose. The purpose of this study was (i) to validate differentially tape-stripped, porcine skin as an in vitro model for the evaluation of transdermal drug delivery (TDD) to premature neonates, (ii) to determine whether the model could estimate neonatal skin permeability as a function of postconceptional age (PCA), and (iii) to demonstrate that iontophoretic delivery permits precise control of drug input independent of skin barrier function.
Methods. Passive permeation of caffeine, phenobarbital, and lidocaine across tape-stripped porcine skin barriers was measured. Iontophoretic delivery of lidocaine across skins with different barrier competencies was also evaluated.
Results. For all drugs, passive permeation correlated with skin barrier function; that is, with transepidermal water loss (TEWL): Jss = A ⋅ exp[B ⋅ TEWL]. Combining this result with a previously derived dependence of TEWL upon the PCA of premature neonates in vivo allowed a relative value of Jss to be predicted for a given PCA. Comparison of these predictions showed excellent agreement with experimental data reported for diamorphine. Iontophoretic lidocaine delivery was precisely controllable independent of barrier competency.
Conclusions. Porcine skin, in vitro, differentially tape-stripped to specific barrier competencies, is a useful model to explore TDD in premature neonates. The potential for iontophoresis to provide improved dose control and adjustment, irrespective of skin barrier maturity, is established.
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- 1.N. Rutter. The immature skin. Eur. J. Pediatr. 155:S18–S20 (1996).Google Scholar
- 2.Y. N. Kalia, L. B. Nonato, C. H. Lund, and R. H. Guy. Development of skin barrier function in premature infants. J. Invest. Dermatol. 111:320–326 (1998).Google Scholar
- 3.M. L. Williams and V. T. Le K. The permeability barrier in the preterm infant. Eur. J. Pediatr. Dermatol. 8:101–106 (1998).Google Scholar
- 4.D. A. Barrett and N. Rutter. Transdermal delivery and the premature neonate. Crit. Rev. Ther. Drug Carrier Syst. 11:1–30 (1994).Google Scholar
- 5.N. J. Evans and N. Rutter. Transdermal drug delivery to the newborn infant. In J. Hadgraft and R. H. Guy (eds.), Transdermal Drug Delivery, Marcel Dekker, New York, 1989, pp. 155–176.Google Scholar
- 6.J. B. Besunder, M. D. Reed, and J. L. Blumer. Principles of drug biodisposition in the neonate: a critical evalutation of the pharmacokinetic-pharmacodynamic interface (Part I). Clin. Pharmacokinet. 14:189–216 (1988).Google Scholar
- 7.N. Barker, J. Hadgraft, and N. Rutter. Skin permeability in the newborn. J. Invest. Dermatol. 88:409–411 (1987).Google Scholar
- 8.N. J. Evans, N. Rutter, J. Hadgraft, and G. Parr. Percutaneous administration of theophylline in the preterm infant. J. Pediatr. 107:307–311 (1985).Google Scholar
- 9.R. G. Cartwright, P. H. Cartlidge, N. Rutter, C. D. Melia, and S. S. Davis. Transdermal delivery of theophylline to premature infants using a hydrogel disc system. Br. J. Clin. Pharmacol. 29: 553–559 (1990).Google Scholar
- 10.M. Amato, M. Isenschmid, and P. Huppi. Percutaneous caffeine application in the treatment of neonatal apnoea. Eur. J. Pediatr. 150:592–594 (1991).Google Scholar
- 11.N. J. Evans and N. Rutter. Development of the epidermis in the newborn. Biol. Neonate 49:74–80 (1986).Google Scholar
- 12.L. B. Nonato. Evolution of Skin Barrier in Premature Neonates,Ph.D Thesis, University of California, Berkeley, 1997.Google Scholar
- 13.N. Sekkat and R. H. Guy. Biological models to study skin permeation. In B.Testa, H. Van de Waterbeemd, G. Folkers, R.H. Guy (eds.), Pharmacokinetic Optimization in Drug Research, Wiley-VCH and VHCA, Zürich, 2001, pp. 155–172.Google Scholar
- 14.N. Sekkat, Y. N. Kalia, and R. H. Guy. Development of an in vitro model for premature neonatal skin: biophysical characterization using transepidermal water loss. J. Pharm. Sci. (2003).Google Scholar
- 15.F. P. Bonina, L. Montenegro, G. Micali, D. P. West, P. Palicharla, and R. L. Koch. In vitro percutaneous absorption evaluation of phenobarbital through hairless mouse, adult and premature human skin. Int. J. Pharm. 98:93–99 (1993).Google Scholar
- 16.P. G. Green, M. Flanagan, B. Shroot, and R. H. Guy. Iontophoretic drug delivery. In K.A. WaltersJ. Hadgraft (eds.), Pharmaceutical Skin Penetration Enhancement, Marcel Dekker, New York, 1993, pp. 311–333.Google Scholar
- 17.P. M. Lai and M. S. Roberts. Iontophoresis. In M.S. Roberts and K. A. Walters (eds.), Dermal Absorption and Toxicity Assessment, Marcel Dekker, New York, 1998, pp. 371–414.Google Scholar
- 18.O. Wong. Iontophoresis: fundamentals. In D.S. Hsieh (ed), Drug Permeation Enhancement, Theory and Applications, Marcel Dekker, New York, 1994, pp. 219–246.Google Scholar
- 19.N. Kanikkannan, J. Singh, and P. Ramarao. In vitro transdermal iontophoretic transport of timolol maleate: effect of age and species. J. Control. Rel. 71:99–105 (2001).Google Scholar
- 20.D. A. Barrett and N. Rutter. Percutaneous lignocaine absorption in newborn infants. Arch. Dis. Child. 71:F122–F124 (1994).Google Scholar
- 21.P. Glikfeld, C. Cullander, R. S. Hinz, and R. H. Guy. A new system for in vitro studies of iontophoresis. Pharm. Res. 5:443–446 (1988).Google Scholar
- 22.A. Naik. Azidoprofen as a Soft Anti-Inflammatory Agent for the Sekkat, Kalia, and Guy 1396 Topical Treatment of Psoriasis.Ph.D Thesis, University of Aston, Birmingham, 1990.Google Scholar
- 23.G. K. Herkes, 496:147–154 (1989).Google Scholar
- 24.D. R. Friend. In vitro skin permeation techniques. J. Control. Rel. 18:235–248 (1992).Google Scholar
- 25.W. R. Ravis. Data interpretation and analysis in percutaneous absorption studies. In B.W. Kemppainen and W. G. Reifenrath (eds.), Methods for Skin Absorption, CRC Press, Boca Raton, 1990, pp. 147–163.Google Scholar
- 26.D. A. Barrett, N. Rutter, and S. S. Davis. An in vitro study of diamorphine permeation through premature human neonatal skin. Pharm. Res. 10:583–587 (1993).Google Scholar
- 27.D. A. Barrett and N. Rutter. Percutaneous lignocaine absorption in newborn infants. Arch. Dis. Child. 71:F122–F124 (1994).Google Scholar
- 28.K. C. Sung, J. Y. Fang, and O. Y. Hu. Delivery of nalbuphine and its prodrugs across skin by passive diffusion and iontophoresis. J. Control. Rel. 67:1–8 (2000).Google Scholar
- 29.D. Marro, Y. N. Kalia, M. B. Delgado-Charro, and R. H. Guy. Contribution of electromigration and electro-osmosis to iontophoretic drug delivery: I. Lidocaine hydrochloride. Pharm. Res. 18:1707–1713 (2001).Google Scholar
- 30.D. Marro, R. H. Guy, and M. B. Delgado-Charro. Characterization of the iontophoretic permselectivity properties of human and pig skin. J. Controlled Release 70:213–217 (2001).Google Scholar
- 31.Y. N. Kalia, L. B. Nonato, C. H. Lund, and R. H. Guy. Development of skin barrier function in premature infants. J. Invest. Dermatol. 111:320–326 (1998).Google Scholar