Restricted accessResearch articleFirst published online 2018-2
Transdermal diffusion,spatial distribution and physical state of a potential anticancer drug in mouse skin as studied by diffusion and spectroscopic techniques
Understanding the efficiency of a transdermal medical drug requires the characterization of its diffusion process, including its diffusion rate, pathways and physical state.
Objective:
The aim of this work is to develop a strategy to achieve this goal.
Methods:
FTIR spectroscopic imaging in conjunction with a Franz cell and HPLC measurements were used to examine the transdermal penetration of deuterated tert-butyl phenylchloroethylurea (tBCEU), a molecule with a potential anticancer action. tBCEU has been solubilized in an expedient solvent mixture and its diffusion in hairless mouse skin has been studied.
Results:
The results indicate that tBCEU diffuses across the skin for more than 10 hours with a rate comparable to selegiline, an officially-approved transdermal drug. IR image analyses reveal that after 10 hours, tBCEU penetrates skin and that its spatial distribution does not correlate with neither the distribution of lipids nor proteins. tBCEU accumulates in cluster domains but overall low concentrations are found in skin. FTIR spectroscopic imaging additionally reveals that tBCEU is in a crystalline form.
Conclusions:
The results suggest that tBCEU is conveyed through the skin without preferential pathway. FTIR spectroscopic imaging and transdermal diffusion measurements appear as complementary techniques to investigate drug diffusion in skin.
AlexeevaN.V. and ArnoldM.A., Near-infrared microspectroscopic analysis of rat skin tissue heterogeneity in relation to noninvasive glucose sensing, J. Diabetes Sci. Technol.3 (2009), 219–232. doi:10.1177/193229680900300202.
2.
AlexeevaN.V. and ArnoldM.A., Impact of tissue heterogeneity on noninvasive near-infrared glucose measurements in interstitial fluid of rat skin, J. Diabetes Sci. Technol.4 (2010), 1041–1054. doi:10.1177/193229681000400503.
3.
AuerM.E.GriesserU.J. and SawatzkiJ., Qualitative and quantitative study of polymorphic forms in drug formulations by near infrared FT-Raman spectroscopy, J. Mol. Struct.661–662 (2003), 307–317. doi:10.1016/j.molstruc.2003.09.002.
4.
BarryB.W., Mode of action of penetration enhancers in human skin, J. Control. Release6 (1987), 85–97. doi:10.1016/0168-3659(87)90066-6.
5.
BarryB.W.EdwardsH.G.M. and WilliamsA.C., Fourier transform Raman and infrared vibrational study of human skin: Assignment of spectral bands, J. Raman Spectrosc.23 (1992), 641–645. doi:10.1002/jrs.1250231113.
6.
BartosovaL. and BajgarJ., Transdermal drug delivery in vitro using diffusion cells, Curr. Med. Chem.19 (2012), 4671–4677. doi:10.2174/092986712803306358.
7.
BassyouniF.ElHalwanyN.Abdel RehimM. and NeyfehM., Advances and new technologies applied in controlled drug delivery system, Res. Chem. Intermed.41 (2013), 2165–2200. doi:10.1007/s11164-013-1338-2.
8.
BéchardP.LacroixJ.PoyetP. and C.-GaudreaultR., Synthesis and cytotoxic activity of new alkyl[3-(2-chloroethyl)ureido]benzene derivatives, Eur. J. Med. Chem.29 (1994), 963–966. doi:10.1016/0223-5234(94)90196-1.
9.
BiaginiF. and CampaninoM., in: Elements of Probability and Statistics, UNITEXTMAT, Vol. 98, 2015, pp. 23–25.
10.
BondJ.R. and BarryB.W., Limitations of hairless mouse skin as a model for in vitro permeation studies through human skin: Hydration damage, J. Invest. Dermatol.90 (1988), 486–489. doi:10.1111/1523-1747.ep12460958.
11.
BurginaE.B.BaltakhinovV.P.BoldyrevaE.V. and ShakhtschneiderT.P., IR spectra of paracetamol and phenacetin. 1. Theoretical and experimental studies, J. Struct. Chem45 (2004), 64–73. doi:10.1023/B:JORY.0000041502.85584.d5.
12.
C.-GaudreaultR.LacroixJ.PagéM. and JolyL.P., 1-aryl-3-(2-chloroethyl) ureas: Synthesis and in vitro assay as potential anticancer agents, J. Pharm. Sci.77 (1988), 185–187. doi:10.1002/jps.2600770218.
13.
DriskellR.R. and WattF.M., Understanding fibroblast heterogeneity in the skin, Trends Cell Biol.25 (2014), 92–99. doi:10.1016/j.tcb.2014.10.001.
14.
DurrheimH.FlynnG.L.HiguchiW.I. and BehlC.R., Permeation of hairless mouse skin I: Experimental methods and comparison with human epidermal permeation by alkanols, J. Pharm. Sci.69 (1980), 781–788. doi:10.1002/jps.2600690709.
15.
Emsam® (segeline transdermal system) – Continuous delivery for once-daily application, 2017, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021336s000_021708s000TOC.cfm, accessed: 2nd October 2017.
16.
FlakM. and WhalleyE., Infrared spectra of methanol and deuterated methanols in gas, liquid, and solid phases, J. Chem. Phys.34 (1961), 1554–1568. doi:10.1063/1.1701044.
17.
GaridelP., Insights in the biochemical composition of skin as investigated by micro infrared spectroscopic imaging, Phys. Chem. Chem. Phys.5 (2003), 2673–2679. doi:10.1039/b302749j.
18.
GaridelP., Structural organisation and phase behaviour of a stratum corneum lipid analogue: Ceramide 3A, Phys. Chem. Chem. Phys.8 (2006), 2265–2275. doi:10.1039/b517540b.
19.
GhoshB.ReddyH.KulkarniR.V. and KhanamJ., Comparison of skin permeability of drugs in mice and human cadaver skin, Indian J. Exp. Biol.38 (2000), 42–45.
20.
GicquaudC.et al., Interaction of 4-tert-butyl-[3-(2-chloroethyl) ureido]benzene with phosphatidylcholine bilayers: A differential scanning calorimetry and infrared spectroscopy study, Arch. Biochem. Biophys.334 (1996), 193–199. doi:10.1006/abbi.1996.0446.
21.
HadgraftJ. and LaneM.E., Drug crystallization – Implications for topical and transdermal delivery, Expert Opin. Drug Del.13 (2016), 817–830.
22.
HeylingsJ.R.et al., Sensitization to 2,4-dinitrochlorobenzene: Influence of vehicle on absorption and lymph node activation, Toxicology109 (1996), 57–65. doi:10.1016/0300-483X(96)03304-5.
23.
HeylingsJ.R.ClowesH.M. and HughesL., Comparison of tissue source for the skin integrity function test (SIFT), Toxicol. in Vitro15 (2001), 597–600. doi:10.1016/S0887-2333(01)00069-8.
24.
KaiT.MakV.H.W.PottsR.O. and GuyR.H., Mechanism of percutaneous penetration enhancement: Effect of n-alkanols on the permeability barrier of hairless mouse skin, J. Control. Release12 (1990), 103–112. doi:10.1016/0168-3659(90)90086-9.
25.
KendallD.N., Identification of polymorphic forms of crystals by infrared spectroscopy, Anal. Chem.25 (1953), 382–389. doi:10.1021/ac60075a002.
26.
KrimmS. and BandekarJ., Vibrational spectroscopy and conformation of peptides, polypeptides, and proteins, Adv. Protein Chem.38 (1986), 181–364. doi:10.1016/S0065-3233(08)60528-8.
LeroyM.et al., A comparative study between human skin substitutes and normal human skin using Raman microspectroscopy, Acta Biomater.10 (2014), 2703–2711. doi:10.1016/j.actbio.2014.02.007.
29.
LeroyM.LafleurM.AugerM.LarocheG. and PouliotR., Characterization of the structure of human skin substitutes by infrared microspectroscopy, Anal. Bioanal. Chem.405 (2013), 8709–8718. doi:10.1007/s00216-013-7103-y.
30.
LeroyM.LefèvreT.PouliotR.AugerM. and LarocheG., Using infrared and Raman microspectroscopies to compare ex vivo involved psoriatic skin with normal human skin, J. Biomed. Opt.20 (2015), 067004. doi:10.1117/1.JBO.20.6.067004.
31.
MendelsohnR.ChenH.C.RerekM.E. and MooreD.J., Infrared microspectroscopic imaging maps the spatial distribution of exogenous molecules in skin, J. Biomed. Opt.8 (2003), 185–190. doi:10.1117/1.1560645.
32.
MendelsohnR.RerekM.E. and MooreD.J., Infrared spectroscopy and microscopic imaging of stratum corneum models and skin, Phys. Chem. Chem. Phys.2 (2000), 4651–4657. doi:10.1039/b003861j.
33.
Miot-NoiraultE.et al., Antineoplastic potency of acrylchloroethylurea derivatives in murine colon carcinoma, Invest. New Drug22 (2004), 369–378. doi:10.1023/B:DRUG.0000036679.12112.4c.
34.
MounetouE.Miot-NoiraultE.C.-GaudreaultR. and MadelmontJ.C., N-4-iodophenyl-N′-2-chloroethylurea, a novel potential anticancer agent with colon-specific accumulation: Radioiodination and comparative in vivo biodistribution profiles, Invest. New Drug28 (2009), 124–131. doi:10.1007/s10637-009-9222-z.
35.
NaikA.PechtoldL.A.R.M.PottsR.O. and GuyR.H., Mechanism of oleic acid-induced skin penetration enhancement in vivo in humans, J. Control. Release37 (1995), 299–306. doi:10.1016/0168-3659(95)00088-7.
36.
NolinB. and JonesR.N., The infrared absorption spectra of diethyl ketone and its deuterium substitution products, J. Am. Chem. Soc.75 (1953), 5626–5628. doi:10.1021/ja01118a046.
PatenaudeA.et al., Chloroethyl urea derivatives block tumour growth and thioredoxin-1 nuclear translocation, Can. J. Physiol. Pharmacol.88 (2010), 1102–1114. doi:10.1139/Y10-084.
39.
PetitclercT.et al., Antiangiogenic and antitumoral activity of phenyl-3-(2-chloroethyl)ureas: A class of soft alkylating agents disrupting microtubules that are unaffected by cell adhesion-mediated drug resistance, Cancer Research64 (2004), 4654–4663. doi:10.1158/0008-5472.CAN-03-3715.
40.
PlivaJ.JohnsJ.W.C. and GoodmanL., High-resolution study of the C–D stretching bands of 12C6D6 and 13C6D6, J. Mol. Spectrosc.163 (1994), 108–118. doi:10.1006/jmsp.1994.1011.
41.
PrausnitzM.R. and LangerR., Transdermal drug delivery, Nat. Biotechnol.26 (2008), 1261–1268. doi:10.1038/nbt.1504.
42.
PrausnitzM.R.MitragotriS. and LangerR., Current status and future potential of transdermal drug delivery, Nat. Rev. Drug Discov.3 (2004), 115–124. doi:10.1038/nrd1304.
43.
PudneyP.D.A.MelotM.CaspersP.J.van der PolA. and PuppelsG.J., An in vivo confocal Raman study of the delivery of trans-retinol to the skin, Appl. Spectrosc.61 (2007), 804–811. doi:10.1366/000370207781540042.
44.
RodgersJ.L. and NicewanderW.A., Thirteen ways to look at the correlation coefficient, Am. Stat.42 (1988), 59–66. doi:10.2307/2685263.
45.
Saint-LaurentA.et al., Membrane interactions of a new class of anticancer agents derived from arylchloroethylurea: A FTIR spectroscopic study, Chem. Phys. Lipids111 (2001), 163–175. doi:10.1016/S0009-3084(01)00154-2.
46.
Saint-LaurentA.BoudreauN.C.-GaudreaultR.PoyetP. and AugerM., Interaction between lipid bilayers and a new class of antineoplastic agents derived from arylchloroethylurea: A 2H solid-state NMR study, Biochem. Cell Biol.76 (1998), 465–471. doi:10.1139/o98-050.
47.
SchaferT.KandratsenkaA.VohringerP.SchroederJ. and SchwarzerD., Vibrational energy relaxation of the ND-stretching vibration of NH2D in liquid NH3, Phys. Chem. Chem. Phys.14 (2012), 11651–11656. doi:10.1039/c2cp41382e.
48.
SchoellhammerC.M.BlankschteinD. and LangerR., Skin permeabilization for transdermal drug delivery: Recent advances and future prospects, Expert Opin. Drug Del.11 (2014), 393–407. doi:10.1517/17425247.2014.875528.
49.
StoughtonR.B., Dimethylsulfoxide (DMSO) – Induction of a steroid reservoir in human skin, Arch. Dermatol.91 (1965), 657–660. doi:10.1001/archderm.1965.01600120089022.
50.
TodoH., Transdermal permeation of drugs in various animal species, Pharmaceutics9 (2017), 33. doi:10.3390/pharmaceutics9030033.
51.
WiedersbergS. and GuyR.H., Transdermal drug delivery: 30+ years of war and still fighting!, J. Control. Release190 (2014), 150–156. doi:10.1016/j.jconrel.2014.05.022.
52.
WilliamsA.C. and BarryB.W., Penetration enhancers, Adv. Drug Deliver. Rev.56 (2004), 603–618. doi:10.1016/j.addr.2003.10.025.
53.
XiaoC.MooreD.J.RerekM.E.FlachC.R. and MendelsohnR., Feasibility of tracking phospholipid permeation into skin using infrared and Raman microscopic imaging, J. Invest. Dermatol.124 (2005), 622–632. doi:10.1111/j.0022-202X.2004.23608.x.
54.
XingM.M.Q.PanN.ZhongW.HuiX. and MaibachH.I., Interfacial kinetics effects on transdermal drug delivery: A computer modeling, Skin Res. Technol.14 (2008), 165–172. doi:10.1111/j.1600-0846.2007.00273.x.
55.
ZhangQ.et al., Infrared spectroscopic imaging tracks lateral distribution in human stratum corneum, Pharm. Res.31 (2014), 2762–2773. doi:10.1007/s11095-014-1373-8.
