메뉴 건너뛰기




Volumn , Issue , 2006, Pages 303-315

Electroporation as a mode of skin penetration enhancement

Author keywords

[No Author keywords available]

Indexed keywords


EID: 77950882527     PISSN: None     EISSN: None     Source Type: Book    
DOI: None     Document Type: Chapter
Times cited : (2)

References (62)
  • 1
    • 0034902043 scopus 로고    scopus 로고
    • Novel mechanisms and devices to enable successful transdermal delivery
    • Barry, B.W. 2001. Novel mechanisms and devices to enable successful transdermal delivery. Eur J Pharm Sci 14:101.
    • (2001) Eur J Pharm Sci , vol.14 , pp. 101
    • Barry, B.W.1
  • 2
    • 0024290394 scopus 로고
    • Structure of lamellar lipid domains and corneocytes envelops of murine stratum corneum. An x-ray diffraction study
    • White, S.H., D. Mirejovsky, and G.I. King. 1988. Structure of lamellar lipid domains and corneocytes envelops of murine stratum corneum. An x-ray diffraction study. Biochemistry 27:3725.
    • (1988) Biochemistry , vol.27 , pp. 3725
    • White, S.H.1    Mirejovsky, D.2    King, G.I.3
  • 3
    • 0028232051 scopus 로고
    • The lipid and protein structure of mouse stratum corneum: A wide and small angle diffraction study
    • Bouwstra, J.A., et al. 1994. The lipid and protein structure of mouse stratum corneum: A wide and small angle diffraction study. Biochim Biophys Acta 1212:183.
    • (1994) Biochim Biophys Acta , vol.1212 , pp. 183
    • Bouwstra, J.A.1
  • 4
    • 0001593336 scopus 로고
    • Iontophoretic drug delivery
    • K.A. Walters, and J. Hadgraft, New York: Marcel Dekker Inc
    • Green, P.G., et al. 1993. Iontophoretic drug delivery. In Pharmaceutical skin penetration enhancement, eds. K.A. Walters, and J. Hadgraft, 311. New York: Marcel Dekker Inc.
    • (1993) Pharmaceutical skin penetration enhancement , pp. 311
    • Green, P.G.1
  • 6
    • 0031959346 scopus 로고    scopus 로고
    • Iontophoresis-recent developments
    • Guy, R.H. 1998. Iontophoresis-recent developments. J Pharm Pharmacol 50:371.
    • (1998) J Pharm Pharmacol , vol.50 , pp. 371
    • Guy, R.H.1
  • 7
    • 0025277768 scopus 로고
    • Transport mechanisms in iontophoresis. III. An experimental study of the contributions of electroosmotic flow and permeability change in transport of low and high molecular weight solutes
    • Pikal, M.J., and S. Shah. 1990. Transport mechanisms in iontophoresis. III. An experimental study of the contributions of electroosmotic flow and permeability change in transport of low and high molecular weight solutes. Pharm Res 7:222.
    • (1990) Pharm Res , vol.7 , pp. 222
    • Pikal, M.J.1    Shah, S.2
  • 8
    • 0025865078 scopus 로고
    • Sites of iontophoretic current flow into the skin: Identification and characterization with the vibrating probe electrode
    • Cullander, C., and R.H. Guy. 1991. Sites of iontophoretic current flow into the skin: Identification and characterization with the vibrating probe electrode. J Invest Dermtol 97:55.
    • (1991) J Invest Dermtol , vol.97 , pp. 55
    • Cullander, C.1    Guy, R.H.2
  • 9
    • 0026928544 scopus 로고
    • What are the pathways of iontophoretic current flow through mammalian skin?
    • Cullander, C. 1992. What are the pathways of iontophoretic current flow through mammalian skin? Adv Drug Deliv Rev 9:119.
    • (1992) Adv Drug Deliv Rev , vol.9 , pp. 119
    • Cullander, C.1
  • 10
    • 0028347849 scopus 로고
    • Identification of the pathway of iontophoretic drug delivery: Light and ultrastructural studies using mercuric chloride in pigs
    • Monteiro-Riviere, N.A., A.O. Inman, and J.E. Riviere. 1994. Identification of the pathway of iontophoretic drug delivery: Light and ultrastructural studies using mercuric chloride in pigs. Pharm Res 11:251.
    • (1994) Pharm Res , vol.11 , pp. 251
    • Monteiro-Riviere, N.A.1    Inman, A.O.2    Riviere, J.E.3
  • 11
    • 0037723904 scopus 로고    scopus 로고
    • Combined chemical and electrical enhancement modulates stratum corneum structure
    • Graaff, A.M., et al. 2003. Combined chemical and electrical enhancement modulates stratum corneum structure. J Control Release 90:49.
    • (2003) J Control Release , vol.90 , pp. 49
    • Graaff, A.M.1
  • 12
    • 0031446133 scopus 로고    scopus 로고
    • Iontophoretic transdermal pathways: Dependence on penetrant physicochemical properties
    • Turner, N.G., and R.H. Guy. 1997. Iontophoretic transdermal pathways: Dependence on penetrant physicochemical properties. J Pharm Sci 86:1385.
    • (1997) J Pharm Sci , vol.86 , pp. 1385
    • Turner, N.G.1    Guy, R.H.2
  • 13
    • 0030071315 scopus 로고    scopus 로고
    • Imaging of fluorescent molecules and small ion transport through human stratum corneum during high voltage pulsing: Localized transport regions are involved
    • Pliquett, U.F., et al. 1996. Imaging of fluorescent molecules and small ion transport through human stratum corneum during high voltage pulsing: Localized transport regions are involved. Biophys Chem 58:185.
    • (1996) Biophys Chem , vol.58 , pp. 185
    • Pliquett, U.F.1
  • 14
    • 0029919085 scopus 로고    scopus 로고
    • Transdermal transport efficiency during skin electroporation and iontophoresis
    • Prausnitz, M.R., et al. 1996. Transdermal transport efficiency during skin electroporation and iontophoresis. J Control Release 38:205.
    • (1996) J Control Release , vol.38 , pp. 205
    • Prausnitz, M.R.1
  • 15
    • 0032852720 scopus 로고    scopus 로고
    • Mechanistic aspects of iontophoresis in human epidermal membrane
    • Higuchi, W.I., et al. 1999. Mechanistic aspects of iontophoresis in human epidermal membrane. J Control Release 62:13.
    • (1999) J Control Release , vol.62 , pp. 13
    • Higuchi, W.I.1
  • 16
    • 0033521640 scopus 로고    scopus 로고
    • Effect of iontophoresis and electroporation on the stratum corneum
    • Jadoul, A., J. Bouwstra, and V. Préat. 1999. Effect of iontophoresis and electroporation on the stratum corneum. Adv Drug Deliv Rev 35:89-105.
    • (1999) Adv Drug Deliv Rev , vol.35 , pp. 89-105
    • Jadoul, A.1    Bouwstra, J.2    Préat, V.3
  • 18
    • 0033521680 scopus 로고    scopus 로고
    • Electropermeabilization of cell membranes
    • Teissié, J., et al. 1999. Electropermeabilization of cell membranes. Adv Drug Deliv Rev 35:3.
    • (1999) Adv Drug Deliv Rev , vol.35 , pp. 3
    • Teissié, J.1
  • 19
    • 0027379355 scopus 로고
    • Electroporation of mammalian skin: A mechanism to enhance transdermal drug delivery
    • Prausnitz, M.R., et al. 1993. Electroporation of mammalian skin: A mechanism to enhance transdermal drug delivery. Proc Natl Acad Sci U S A 90:10504.
    • (1993) Proc Natl Acad Sci U S A , vol.90 , pp. 10504
    • Prausnitz, M.R.1
  • 20
    • 0028352235 scopus 로고
    • Studies on the effects of applied voltage and duration on human epidermal membrane alteration/recovery and the resultant effects upon iontophoresis
    • Inada, H., W.I. Higuchi, and A. Ghanem. 1994. Studies on the effects of applied voltage and duration on human epidermal membrane alteration/recovery and the resultant effects upon iontophoresis. Pharm Res 11:687.
    • (1994) Pharm Res , vol.11 , pp. 687
    • Inada, H.1    Higuchi, W.I.2    Ghanem, A.3
  • 21
    • 0028130432 scopus 로고
    • Transdermal delivery of metoprolol by electroporation
    • Vanbever, R., N. Lecoutturier, and V. Préat. 1994. Transdermal delivery of metoprolol by electroporation. Pharm Res 11:1657.
    • (1994) Pharm Res , vol.11 , pp. 1657
    • Vanbever, R.1    Lecoutturier, N.2    Préat, V.3
  • 22
    • 0030000445 scopus 로고    scopus 로고
    • Transdermal delivery of fentanyl by electroporation. I. Influence of electrical factors
    • Vanbever, R., E. Le Boulengé, and V. Préat. 1996. Transdermal delivery of fentanyl by electroporation. I. Influence of electrical factors. Pharm Res 13:559.
    • (1996) Pharm Res , vol.13 , pp. 559
    • Vanbever, R.1    Le Boulengé, E.2    Préat, V.3
  • 23
    • 0032516673 scopus 로고    scopus 로고
    • Transdermal penetration of neutral molecules by skin electroporation
    • Vanbever, R., M. Leroy, and V. Préat. 1998. Transdermal penetration of neutral molecules by skin electroporation. J Control Release 54:243.
    • (1998) J Control Release , vol.54 , pp. 243
    • Vanbever, R.1    Leroy, M.2    Préat, V.3
  • 24
    • 0033521602 scopus 로고    scopus 로고
    • Theory of electrical creation of pathways across skin transport barriers
    • Weaver, J.C., T.E. Vaughan, and Y. Chizmadzhev. 1999. Theory of electrical creation of pathways across skin transport barriers. Adv Drug Deliv Rev 35:21.
    • (1999) Adv Drug Deliv Rev , vol.35 , pp. 21
    • Weaver, J.C.1    Vaughan, T.E.2    Chizmadzhev, Y.3
  • 25
    • 0033521545 scopus 로고    scopus 로고
    • A practical assessment of transdermal drug delivery by skin electroporation
    • Prausnitz, M.R. 1999. A practical assessment of transdermal drug delivery by skin electroporation. Adv Drug Deliv Rev 35:61.
    • (1999) Adv Drug Deliv Rev , vol.35 , pp. 61
    • Prausnitz, M.R.1
  • 26
    • 0032450651 scopus 로고    scopus 로고
    • Skin electroporation causes molecular transport across the stratum corneum through localised regions
    • Chen, T., R. Langer, and J.C. Weaver. 1998. Skin electroporation causes molecular transport across the stratum corneum through localised regions. J Investig Dermatol Symp Proc 3:159.
    • (1998) J Investig Dermatol Symp Proc , vol.3 , pp. 159
    • Chen, T.1    Langer, R.2    Weaver, J.C.3
  • 27
    • 0028950699 scopus 로고
    • Mechanism of electroinduced ionic species transport through a multilamellar lipid system
    • Chizmadzhev, Y., et al. 1995. Mechanism of electroinduced ionic species transport through a multilamellar lipid system. Biophys J 68:749.
    • (1995) Biophys J , vol.68 , pp. 749
    • Chizmadzhev, Y.1
  • 28
    • 0030574682 scopus 로고    scopus 로고
    • The effects of electric current applied to the skin: A review for transdermal drug delivery
    • Prausnitz, M.R. 1996. The effects of electric current applied to the skin: A review for transdermal drug delivery. Adv Drug Deliv Rev 18:395.
    • (1996) Adv Drug Deliv Rev , vol.18 , pp. 395
    • Prausnitz, M.R.1
  • 29
    • 0033521683 scopus 로고    scopus 로고
    • Mechanistic studies of molecular transdermal transport due to skin electroporation
    • Pliquett, U. 1999. Mechanistic studies of molecular transdermal transport due to skin electroporation. Adv Drug Deliv Rev 35:41.
    • (1999) Adv Drug Deliv Rev , vol.35 , pp. 41
    • Pliquett, U.1
  • 30
    • 0034112255 scopus 로고    scopus 로고
    • Perturbation of human skin due to application of high voltages
    • Pliquett, U.F., and C.A. Gusbeth. 2000. Perturbation of human skin due to application of high voltages. Bioelectrochemistry 51:41.
    • (2000) Bioelectrochemistry , vol.51 , pp. 41
    • Pliquett, U.F.1    Gusbeth, C.A.2
  • 31
    • 0032215553 scopus 로고    scopus 로고
    • Local transport regions in human stratum corneum due to long and short “high voltage” pulses
    • Pliquett, U., et al. 1998. Local transport regions in human stratum corneum due to long and short “high voltage” pulses. Bioelectrochem Bioenerg 47:151.
    • (1998) Bioelectrochem Bioenerg , vol.47 , pp. 151
    • Pliquett, U.1
  • 32
    • 0036016316 scopus 로고    scopus 로고
    • Kinetics of the temperature rise within human stratum corneum during electroporation and pulsed high voltage iontophoresis
    • Pliquett, U.F., G.T. Martin, and J.C. Weaver. 2002. Kinetics of the temperature rise within human stratum corneum during electroporation and pulsed high voltage iontophoresis. Bioelectrochemistry 57:65.
    • (2002) Bioelectrochemistry , vol.57 , pp. 65
    • Pliquett, U.F.1    Martin, G.T.2    Weaver, J.C.3
  • 33
    • 0002116818 scopus 로고    scopus 로고
    • Electroporation of human skin: Simultaneous measurement of changes in the transport of two fluorescent molecules and in the passive electrical properties
    • Pliquett, U.F., and J.C. Weaver. 1996. Electroporation of human skin: Simultaneous measurement of changes in the transport of two fluorescent molecules and in the passive electrical properties. Bioelectrochem Bioenerg 39:1.
    • (1996) Bioelectrochem Bioenerg , vol.39 , pp. 1
    • Pliquett, U.F.1    Weaver, J.C.2
  • 34
    • 0345434850 scopus 로고    scopus 로고
    • In vivo efficacy and safety of skin electroporation
    • Préat, V., and R. Vanbever. 1999. In vivo efficacy and safety of skin electroporation. Adv Drug Deliv Rev 35:77.
    • (1999) Adv Drug Deliv Rev , vol.35 , pp. 77
    • Préat, V.1    Vanbever, R.2
  • 36
    • 0037423781 scopus 로고    scopus 로고
    • Transdermal delivery of timolol by electroporation through human skin
    • Denet, A., and V. Préat. 2003. Transdermal delivery of timolol by electroporation through human skin. J Control Release 88:253.
    • (2003) J Control Release , vol.88 , pp. 253
    • Denet, A.1    Préat, V.2
  • 37
    • 0003000862 scopus 로고    scopus 로고
    • Transdermal delivery of fluriprofen in the rat by iontophoresis and electroporation
    • Cruz, M.P., et al. 1997. Transdermal delivery of fluriprofen in the rat by iontophoresis and electroporation. Pharm Res 14:309.
    • (1997) Pharm Res , vol.14 , pp. 309
    • Cruz, M.P.1
  • 38
    • 0030964989 scopus 로고    scopus 로고
    • Topical delivery of cyclosporin A co-evaporate using electroporation technique
    • Wang, S., M. Kara, and T.R. Krishnan. 1997. Topical delivery of cyclosporin A co-evaporate using electroporation technique. Drug Dev Ind Pharm 23:657.
    • (1997) Drug Dev Ind Pharm , vol.23 , pp. 657
    • Wang, S.1    Kara, M.2    Krishnan, T.R.3
  • 39
    • 14744287956 scopus 로고
    • Transdermal delivery of heparin by skin electroporation
    • Prausnitz, M.R., et al. 1995. Transdermal delivery of heparin by skin electroporation, Biotechnology 13:1205.
    • (1995) Biotechnology , vol.13 , pp. 1205
    • Prausnitz, M.R.1
  • 40
    • 0031889133 scopus 로고    scopus 로고
    • Effects of size and sequence on the iontophoretic delivery of oligonucleotides
    • Brand, R.M., A. Wahl, and P.L. Iverson. 1998. Effects of size and sequence on the iontophoretic delivery of oligonucleotides. J Pharm Sci 87:49.
    • (1998) J Pharm Sci , vol.87 , pp. 49
    • Brand, R.M.1    Wahl, A.2    Iverson, P.L.3
  • 43
    • 0037133103 scopus 로고    scopus 로고
    • In vivo assessment of skin electroporation using square wave pulses
    • Dujardin, N., et al. 2002. In vivo assessment of skin electroporation using square wave pulses. J Control Release 79:219.
    • (2002) J Control Release , vol.79 , pp. 219
    • Dujardin, N.1
  • 44
    • 0033006887 scopus 로고    scopus 로고
    • Iontophoresis and electroporation: Comparisons and contrasts
    • Banga, A.K., S. Bose, and T.K. Ghosh. 1999. Iontophoresis and electroporation: Comparisons and contrasts. Int J Pharm 179:1.
    • (1999) Int J Pharm , vol.179 , pp. 1
    • Banga, A.K.1    Bose, S.2    Ghosh, T.K.3
  • 45
    • 0028020044 scopus 로고
    • Effect of electroporation on transdermal iontophoretic delivery of luteinizing hormone releasing hormone (LHRH) in vitro
    • Bommannan, D.B., et al. 1994. Effect of electroporation on transdermal iontophoretic delivery of luteinizing hormone releasing hormone (LHRH) in vitro. Pharm Res 11:1809.
    • (1994) Pharm Res , vol.11 , pp. 1809
    • Bommannan, D.B.1
  • 46
    • 0028881057 scopus 로고
    • Pulsatile transdermal delivery of LHRH using electroporation: Drug delivery and skin toxicology
    • Riviere, J.E., et al. 1995. Pulsatile transdermal delivery of LHRH using electroporation: Drug delivery and skin toxicology. J Control Release 40:229.
    • (1995) J Control Release , vol.40 , pp. 229
    • Riviere, J.E.1
  • 47
    • 0034657103 scopus 로고    scopus 로고
    • The effect of electroporation on iontophoretic transdermal delivery of calcium regulating hormones
    • Chang, S.L., et al. 2000. The effect of electroporation on iontophoretic transdermal delivery of calcium regulating hormones. J Control Release 66:127.
    • (2000) J Control Release , vol.66 , pp. 127
    • Chang, S.L.1
  • 48
    • 0036313791 scopus 로고    scopus 로고
    • Effect of electroporation and iontophoresis on skin permeation of Defibrase- a purified thrombin-like enzyme from the venom of Agkistrodon halys ussuriensis Emelianov
    • Zhao, H.Y., et al. 2002. Effect of electroporation and iontophoresis on skin permeation of Defibrase- a purified thrombin-like enzyme from the venom of Agkistrodon halys ussuriensis Emelianov. Pharmazie 57:482.
    • (2002) Pharmazie , vol.57 , pp. 482
    • Zhao, H.Y.1
  • 49
    • 0035990529 scopus 로고    scopus 로고
    • Electrically enhanced transepidermal delivery of a macromolecule
    • Badkar, A.V., and A.J. Banga. 2002. Electrically enhanced transepidermal delivery of a macromolecule. J Pharm Pharmacol 54:907.
    • (2002) J Pharm Pharmacol , vol.54 , pp. 907
    • Badkar, A.V.1    Banga, A.J.2
  • 50
    • 0032987546 scopus 로고    scopus 로고
    • Charged microbeads are not transported across the human stratum corneum in vitro by short high-voltage pulses
    • Cheng, T., R. Langer, and J.C. Weaver. 1999. Charged microbeads are not transported across the human stratum corneum in vitro by short high-voltage pulses. Bioelectrochem Bioenerg 48:181.
    • (1999) Bioelectrochem Bioenerg , vol.48 , pp. 181
    • Cheng, T.1    Langer, R.2    Weaver, J.C.3
  • 51
    • 0037139420 scopus 로고    scopus 로고
    • Transepidermal iontophoresis of sodium nonivamide acetate V. Combined effect of physical enhancement methods
    • Fang, J.Y., et al. 2002. Transepidermal iontophoresis of sodium nonivamide acetate V. Combined effect of physical enhancement methods. Int J Pharm 235:95.
    • (2002) Int J Pharm , vol.235 , pp. 95
    • Fang, J.Y.1
  • 52
    • 0024555620 scopus 로고
    • Examination of iontophoretic transport of ionic drugs across skin: Baseline studies with the four-electrode system
    • Masada, T., et al. 1989. Examination of iontophoretic transport of ionic drugs across skin: Baseline studies with the four-electrode system. Int J Pharm 49:57.
    • (1989) Int J Pharm , vol.49 , pp. 57
    • Masada, T.1
  • 53
    • 0030914876 scopus 로고    scopus 로고
    • Iontophoretic transport across a synthetic membrane and human epidermal membrane: A study of the effects of permeant charge
    • Li, K.S., et al. 1997. Iontophoretic transport across a synthetic membrane and human epidermal membrane: A study of the effects of permeant charge. J Pharm Sci 86:680.
    • (1997) J Pharm Sci , vol.86 , pp. 680
    • Li, K.S.1
  • 54
    • 0028849109 scopus 로고
    • Changes in the passive electrical properties of human stratum corneum due to electroporation
    • Pliquett, U., R. Langer, and J.C. Weaver. 1995. Changes in the passive electrical properties of human stratum corneum due to electroporation. Biochim Biophys Acta 1239:111.
    • (1995) Biochim Biophys Acta , vol.1239 , pp. 111
    • Pliquett, U.1    Langer, R.2    Weaver, J.C.3
  • 55
    • 0029922803 scopus 로고    scopus 로고
    • Do high voltages cause changes in skin structure?
    • Prausnitz, M.R. 1996. Do high voltages cause changes in skin structure? J Control Release 40:321.
    • (1996) J Control Release , vol.40 , pp. 321
    • Prausnitz, M.R.1
  • 56
    • 0343035668 scopus 로고    scopus 로고
    • Electrically enhanced transdermal delivery of domperidone
    • Jadoul, A., and V. Préat. 1997. Electrically enhanced transdermal delivery of domperidone. Int J Pharm 154:229.
    • (1997) Int J Pharm , vol.154 , pp. 229
    • Jadoul, A.1    Préat, V.2
  • 57
    • 0034691812 scopus 로고    scopus 로고
    • Enhanced transdermal delivery of tetracaine by electroporation
    • Hu, Q., et al. 2000. Enhanced transdermal delivery of tetracaine by electroporation. Int J Pharm 202:121.
    • (2000) Int J Pharm , vol.202 , pp. 121
    • Hu, Q.1
  • 58
    • 0030902518 scopus 로고    scopus 로고
    • Macromolecules as novel transdermal transport enhancers for skin electroporation
    • Vanbever, R., M.R. Prausnitz, and V. Preat. 1997. Macromolecules as novel transdermal transport enhancers for skin electroporation. Pharm Res 14:638.
    • (1997) Pharm Res , vol.14 , pp. 638
    • Vanbever, R.1    Prausnitz, M.R.2    Preat, V.3
  • 59
    • 4644290585 scopus 로고    scopus 로고
    • Cyclodextrin enhanced transdermal delivery of piroxicam and carboxyfluorescein by electroporation
    • Murthy, S.N., et al. 2004. Cyclodextrin enhanced transdermal delivery of piroxicam and carboxyfluorescein by electroporation. J Control Release 99:393.
    • (2004) J Control Release , vol.99 , pp. 393
    • Murthy, S.N.1
  • 60
    • 1242289359 scopus 로고    scopus 로고
    • The effects of calcium chloride and sodium chloride on the electroporation-mediated skin permeation of fluorescein isothiocyanate (FITC)-dextrans in vitro
    • Tokudome, Y., and K. Sugibayashi. 2003. The effects of calcium chloride and sodium chloride on the electroporation-mediated skin permeation of fluorescein isothiocyanate (FITC)-dextrans in vitro. Biol Pharm Bull 26:1508.
    • (2003) Biol Pharm Bull , vol.26 , pp. 1508
    • Tokudome, Y.1    Sugibayashi, K.2
  • 61
    • 0033034043 scopus 로고    scopus 로고
    • Enhancement of transdermal iontophoretic delivery of a liposomal formulation of colchicine by electroporation
    • Badkar, A.V., et al. 1999. Enhancement of transdermal iontophoretic delivery of a liposomal formulation of colchicine by electroporation. Drug Deliv 6:111.
    • (1999) Drug Deliv , vol.6 , pp. 111
    • Badkar, A.V.1
  • 62
    • 0141741634 scopus 로고    scopus 로고
    • Electroporation and ultradeformable liposomes; human skin repair by phospholipid
    • Essa, E.A., M.C. Bonner, and B.W. Barry. 2003. Electroporation and ultradeformable liposomes; human skin repair by phospholipid. J Control Release 92:163.
    • (2003) J Control Release , vol.92 , pp. 163
    • Essa, E.A.1    Bonner, M.C.2    Barry, B.W.3


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.