Abstract
Purpose. Several studies have suggested epidermal uptake of cytokines, such as interferons, can be facilitated using topical liposomal formulations. We have evaluated the in vitro transport of biologically active recombinant human interferon-γ (rhIFN-γ) into and through split-thickness human skin to assess this possibility.
Methods. Skin samples were exposed to rhIFN-γ under various conditions involving hydrated and dry surface conditions in the presence and absence of liposomes. A new low-level ELISA and an anti-viral bioassay were used to quantitate transported rhIFN-γ. Immunohistochemical staining for ICAM-1 expression by keratinocytes was used to visualize the extent and distribution of rhIFN-γ transport.
Results. Apparent steady-state transport of rhIFN-γ occurred within the first 5 hours of exposure with approximately 10% of transported rhIFN-γ demonstrating bioactivity. While the permeability of rhIFN-γ across human skin under drying conditions was enhanced by the presence of liposomes, no augmentation of permeability was observed when the skin was kept hydrated. Liposomal formulations of rhIFN-;γ had greater transport rates than aqueous formulations when the applied formulations were allowed to dry after dosing.
Conclusions. Our results demonstrate the transport of biologically active rhIFN-γ across human skin in vitro and suggest a role for stratum corneum hydration as one possibility for the augmented cytokine transport.
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REFERENCES
J.M. Hanifin, L.C. Schneider, D.Y.M. Leung, C.N. Ellis, H.S. Jaffe, A.E. Izu, L.R. Bucalo, L.R. Hirabayashi, S.J. Tofte, G. Cantu Gonzales, H. Milgrom, M. Boguniewicz, K.D. Cooper. Recombinant interferon gamma therapy for atopic dermatitis. J. Am. Acad. Dermatol. 28:189–197 (1993).
R.D. Granstein, A. Rook, T.J. Flotte, A. Haas, R.L. Gallo, H.S. Jaffe, E.P. Amento. A controlled trial of intralesional recombinant interferon-γ in the treatment of keloidal scarring. Arch. Dermatol. 126:1295–1302 (1990).
U. Reinhold, S. Kukel, B. Goeden, U. Neumann, H.W. Kreysel. Functional characterization of skin-infiltrating lymphocytes in atopic dermatitis. Clin. Exp. Immunol. 86:444–448 (1991).
S. Kakumu, T. Ishikawa, M. Mizokami, E. Orido, K. Yoshioka, T. Wakita, M. Yamamoto. Treatment with human gamma interferon of chronic hepatitis B: Comparative study with alpha interferon. J. Med. Virology 35:32–37 (1991).
P.G. O'Connell, L.H. Gerber, J.J. Digiovanna, G.L. Peck. Arthritis in patients with psoriasis treated with gamma-interferon. J. Rheumatol. 19:80–82 (1992).
P.M. Elias, D.S. Friend. The permeability barrier in mammalian epidermis. J. Cell Biol. 65:180–191 (1975).
P.M. Elias, J. Goerke, D.S. Friend. Mammalian epidermal barrier layer lipids: composition and influence on structure. J. Invest. Dermatol. 69:535–546 (1977).
K.V. Roskos, R.H. Guy. Assessment of skin barrier function using transepidermal water loss: effect of age. Pharm. Res. 6:949–953 (1989).
A.C. Williams, B.W. Barry. Skin Absorption Enhancers. Crit. Rev. in Therap. Drug Carrier Syst. 9:305–355 (1992).
Y-C.J. Wang, M.A. Hanson. Parenteral formulations of proteins and peptides: stability and stabilizers. J. Parenteral Sci. Technol. 42:S3–S26 (1988).
M.C. Manning, K. Patel, R.T. Borchardt. Stability of protein pharmaceutics. Pharm. Res. 6:903–918 (1989).
N. Weiner, N. Williams, G. Birch, C. Ramachandran, C. Shipman Jr., G. Flynn. Topical delivery of liposomally encapsulated α-interferon in a cutaneous herpes guinea pig model. Antimicro. Agents Chemother. 33:1217–1221 (1989).
J. du Pleiss, K. Egbaria, C. Ramachandran, N. Weiner. Topical delivery of liposomally encapsulated gamma-interferon. Antiviral Res. 18:259–265 (1992).
R.A. Schwendener. The preparation of large volumes of homogeneous, sterile liposomes containing various lipophilic cytostatic drugs by the use of a capillary dialyzer. Cancer Drug Delivery 3:123–129 (1986).
M.L. Francoeur, R.O. Potts. The influence of stratum corneum morphology on water permeability. J. Invest. Dermatol. 96:495–499 (1991).
G.M. Grass, S.A. Sweetana. In vitro measurement of gastrointestinal tissue permeability using a new diffusion cell. Pharm. Res. 5:372–376 (1988).
M.B. Wilson, P.K. Nakane. Recent developments in the periodate method of conjugating horseradish peroxidase (HPO) to antibodies, in “Immunofluorescence and related staining techniques” W. Knapp, K. Holubar, G. Wicks, eds. Elsevier/North-Holland Biomedical Press, pp. 215–224 (1987).
D. Marquardt. An algorithm for least-square estimation of nonlinear parameters. J. Soc. Indust. Appl. Math 11:431–441 (1963).
N.H. McManus. Microtiter assay for interferon: microspectro-photometric quantitation of cytopathic effect. Appl. Environ. Microbiol. 31:35 (1976).
A.P. Winiski, C.A. Foster. ICAM-1 expression in a spontaneously transformed human keratinocyte cell line: characterization by a simple cell-ELISA assay. J. Invest. Dermatol. 99:48–52 (1992).
A. Scheynius, J. Fransson, C. Johansson, H. Hammar, B. Baker, L. Fry, H. Valdimarsson. Expression of interferongamma receptors in normal and psoriatic skin. J. Invest. Dermatol. 98:255–258 (1992).
H. Lortat-Jacob, J.-A. Grimaud. Interferon-γ binds to heparin sulfate by a cluster of amino acids located in the C-terminal part of the molecule. FEBS LETTERS 280:152–154 (1991).
S-K. Chang, J.E. Riviere. Effect of humidity and occlusion on the percutaeous absorption of parathion in vitro. Pharm. Res. 10:152–155 (1993).
D.A.W. Bucks, H.I. Maibach, R.H. Guy. Occlusion does not uniformly enhance penetration in vivo, in “Percutaneous absorption” R.L. Bronough, H.I. Maibach, eds. Marcel Dekker, New York, p. 87, (1989).
Y. Morimoto, T. Hatanaka, K. Sugibayashi, H. Omiya. Prediction of skin permeability of drugs: comparison of human and hairless rat skin. J. Pharm. Pharmacol. 44:634–639 (1992).
K. Harada, T. Murakami, N. Yata, S. Yamamoto. Role of intercellular lipids in stratum corneum in the percutaneous permeation of drugs. J. Clin. Invest. 99:278–282 (1992).
B. Ongpipattanakul, R.R. Burnette, R.O. Potts, M.L. Francoeur. Evidence that oleic acid exists in a separate phase within stratum corneum lipids. Pharm. Res. 8:350–354 (1991).
V. Masini, F. Bonte, A. Meybeck, J. Wepierre. Cutaneous bioavailability in hairless rats of tretinoin in liposomes or gel. J. Pharm. Sci. 82:17–21 (1993).
C. Michel, T. Purmann, E. Mentrup, E. Seiller, J. Kreuter. Effect of liposomes on percutaneous penetration of lipophilic materials. Int. J. Pharm. 84:93–105 (1992).
J. Lasch, R. Laub, W. Wohlrab. How deep do intact liposomes penetrate into human skin? J. Contr. Rel. 18:55–58 (1991).
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Short, S.M., Rubas, W., Paasch, B.D. et al. Transport of Biologically Active Interferon-gamma Across Human Skin in Vitro. Pharm Res 12, 1140–1145 (1995). https://doi.org/10.1023/A:1016408508290
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DOI: https://doi.org/10.1023/A:1016408508290