Abstract
There are at least 15 factors that influence the ability of chemicals to penetrate the skin. Substantivity is yet another factor and allows penetrants to remain on and in skin for many days. As many skin pathologies involve stratum corneum and require multiple dosing of topicals, understanding substantivity mechanisms may provide insight for topical dosing strategies. Substantivity is also of importance in the development of other consumer products that necessitate adherence to skin, including sunscreens, insect repellents, and cosmetics. Furthermore, while stratum corneum adherence may delay percutaneous penetration, reducing the risk of systemic toxicity, excessive substantivity may play a role in the toxic accumulation of harmful penetrants. Continued research in this area may offer insight into dermatotoxicology and dermatopharmacology.
Similar content being viewed by others
References
Aalto-Korte K (1995) Improvement of skin barrier function during treatment of atopic dermatitis. J Am Acad Dermatol 33:969–972
Aly R, Maibach HI (1979) Comparative study on the antimicrobial effect of 0.5% chlorhexidine gluconate and 70% isopropyl alcohol on the normal flora of hands. Appl Environ Microbiol 37(3):610–613
Arancibia A, Borie G, Cornwell E, Medrano C (1981) Pharmacokinetic study on the percutaneous absorption of p-aminobenzoic acid from three sunscreen preparations. Farmaco Prat 36(8):357–365
Baldwin JN, Rheins MS, Sylvester RF Jr, Shaffer TE (1957) Staphylococcal infections in newborn infants. AMA J Dis Child 94(2):107–116
Benech-Kieffer F, Wegrich P, Schwarzenbach R, Klecak G, Weber T, Leclaire J, Schaefer H (2000) Percutaneous absorption of sunscreens in vitro: interspecies comparison, skin models and reproducibility aspects. Skin Pharmacol Appl Skin Physiol 13(6):324–335. https://doi.org/10.1159/000029940
Biebl KA, Warshaw EM (2006) Allergic contact dermatitis to cosmetics. Dermatol Clin 24(2):215–232. https://doi.org/10.1016/j.det.2006.01.006
Bollinger JN, Seelig LL (1970) Adherence of vegetable bath oils to keratin. J Soc Cosmet Chem 21(9):613–623
Boosalis M, McCall J, Ahrenholz D, Solem L, McClain C (1987) Serum and urinary silver levels in thermal injury patients. Surgery 101:40–43
Bottari F, Nannipieri E, Saettone MF, Serafini MF (1978) Substantivity of sunscreens: a study on the interaction of four alkyl 4-aminobenzoates with keratin. J Soc Cosmet Chem 29:353–363
Brieva H, Russ JG, Sandewicz IM (2004) Cosmetic compositions. US Patent 6:780,422
Cao Y, Elmahdy A, Zhu H, Hui X, Maibach H (2018) Binding affinity and decontamination of dermal decontamination gel to model chemical warfare agent simulants. J Appl Toxicol. https://doi.org/10.1002/jat.3580
Carroll FE Jr, Salak WW, Howard JM, Pairent FW (1967) Absorption of antimicrobial agents across experimental wounds. Surg Gynecol Obstet 125(5):974–978
Chilcote R, Curley A, Loughlin HH, Jupin JA (1977) Hexachlorophene storage in a burn patient associated with encephalopathy. Pediatrics 59(3):457–459
Cumpelik B (1976) Substantivity of sunscreens. Cosmet Toilet 91:59–62
de Gennes PG (2001) Ultradivided matter. Nature 412(6845):385. https://doi.org/10.1038/35086662
Drechsler LE, Rabe TE, Smith ED (2000) Transfer resistant cosmetic compositions. US Patent 6:071,503
Farquharson CD, Penny SF, Edwards HE, Barr E (1952) The control of staphylococcal skin infections in the nursery. Can Med Assoc J 67(3):247–249
Feldmann RJ, Maibach HI (1965) Penetration of 14C hydrocortisone through normal skin: the effect of stripping and occlusion. Arch Dermatol 91:661–666
Feldmann RJ, Maibach HI (1970) Absorption of some organic compounds through the skin in man. J Investig Dermatol 54(5):399–404. https://doi.org/10.1111/1523-1747.ep12259184
Flynn GL, Behl CR, Walters KA, Gatmaitan OG, Wittkowsky A, Kurihara T, Ho NF, Higuchi WI, Pierson CL (1980) Permeability of thermally damaged skin III: influence of scalding temperature on mass transfer of water and n-alkanols across hairless mouse skin. Burns 8:47–58
Gattu S, Maibach HI (2010) Enhanced absorption through damaged skin: an overview of the in vitro human model. Skin Pharmacol Physiol 23(4):171–176
Gattu S, Maibach HI (2011) Modest but increased penetration through damaged skin: an overview of the in vivo human model. Skin Pharmacol Physiol 24(1):2–9. https://doi.org/10.1159/000314995
Gluck L, Wood HF (1961) Effect of an antiseptic skin-care regimen in reducing in reducing staphylococcal colonization in newborn infants. N Engl J Med 265(24):1177–1181. https://doi.org/10.1056/NEJM196112142652402
Goddard E, Faucher J, Scott R, Turney M (1975) Adsorption of polymer JR on keratinous surfaces—Part II. J Soc Cosmet Chem 26:539–550
Gonzalez H, Farbrot A, Larko O, Wennberg AM (2006) Percutaneous absorption of the sunscreen benzophenone-3 after repeated whole-body applications, with and without ultraviolet irradiation. Br J Dermatol 154(2):337–340. https://doi.org/10.1111/j.1365-2133.2005.07007.x
Goossens A, Beck MH, Haneke E, McFadden JP, Nolting S, Durupt G, Ries G (1999) Adverse cutaneous reactions to cosmetic allergens. Contact Dermat 40(2):112–113
Goutieres F, Aicardi J (1977) Accidental percutaneous hexachlorophane intoxication in children. Br Med J 2(6088):663–665. https://doi.org/10.1136/bmj.2.6088.663
Gump WS (1945) The development of a germicidal soap. Soap Sanit Chem 21:36–50
Gump WS (1969) Toxicological properties of hexachlorophene. J Soc Cosmet Chem 20(3):173–184
Gupta VK, Zatz JL, Rerek M (1999) Percutaneous absorption of sunscreens through micro-Yucatan pig skin in vitro. Pharm Res 16(10):1602–1607. https://doi.org/10.1023/A:1018916907263
Havens I, Benham RS, Clark DE (1957) Hexachlorophene in the surgical scrub. Am J Med Technol 23(2):76–86
Hay RJ, Johns NE, Williams HC, Bolliger IW, Dellavalle RP, Margolis DJ, Mark R, Naldi L, Weinstock MA, Wulf SK, Michaud C, Murray CJL, Naghavi M (2014) The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions. J Investig Dermatol 134:1527–1534
Hayden CG, Roberts MS, Benson HA (1997) Systemic absorption of sunscreen after topical application. Lancet 350(9081):863–864. https://doi.org/10.1016/S0140-6736(05)62032-6
Heneweer M, Muusse M, van den Berg M, Sanderson JT (2005) Additive estrogenic effects of mixtures of frequently used UV filters on pS2-gene transcription in MCF-7 cells. Toxicol Appl Pharmacol 208:170–177
Herter WB (1959) Hexachlorophene poisoning. Kaiser Found Med Bull 7:228
Jakasa I, Verberk M, Bunge A, Kruse J, Kezić S (2006) Increased permeability for polyethylene glycols through skin compromised by sodium lauryl sulphate. Exp Dermatol 15:801–807
Kienzler JL, Queille-Roussel C, Mugglestone C, Ortonne JP, Larnier C (2007) Stratum corneum pharmacokinetics of the anti-fungal drug, terbinafine, in a novel topical formulation, for single-dose application in dermatophytoses. Curr Med Res Opin 23(6):1293–1302. https://doi.org/10.1185/030079907X199664
Kimbrough RD (1971) Review of the toxicity of hexachlorophene. Arch Environ Health 23(2):119–122. https://doi.org/10.1080/00039896.1971.10665967
Klammer H, Schlecht C, Wuttke W, Jarry H (2005) Multi-organic risk assessment of estrogenic properties of octyl-methoxycinnamate in vivo. A 5-day sub-acute pharmacodynamic study with ovariectomized rats. Toxicology 215:90–96
Koch FC, Hanke ME (1948) Practical methods in biochemistry, 5th edn. Williams And Wilkins Company, Baltimore
Krzysik DG (1994) Cosmetics with enhanced durability. US Patent 5:330,747
Kunz PY, Fent K (2006) Estrogenic activity of UV filter mixtures. Toxicol Appl Pharmacol 217:86–99
Larose P, Fischer R (1952) A test for bactericidal activity in which bacteria are replaced by wool. Research (London) 5:419–423
Larson DL (1968) Studies show hexachlorophene causes burn syndrome. Hospitals 42(24):63–64
Larson DL, Abston S, Bachmann RC (1971) Hexachlorophene absorption from the burn wound. In: Matter P, Barclay TL, Konickova Z (eds) Research in burns. Hans Huber, Vienna, p 619
Lewis DJ, Feldman SR (2017) Practical ways to improve patient adherence. CreateSpace Independent Publishing Platform, Middletown
Leyden JJ, Stewart R, Kligman AM (1979) Updated in vivo methods for evaluating topical antimicrobial agents on human skin. J Investig Dermatol 72(4):165–170. https://doi.org/10.1111/1523-1747.ep12676347
Lockhart SP, Rushworth A, Azmy AA, Raine PA (1983) Topical silver sulphadiazine: side effects and urinary excretion. Burns Incl Therm Inj 10:9–12
Lunter DJ, Rottke M, Daniels R (2014) Oil-in-oil-emulsions with enhanced substantivity for the treatment of chronic skin diseases. J Pharm Sci 103(5):1515–1519. https://doi.org/10.1002/jps.23944
Maibach HI, Kligman AM (1960) Dihydroxyacetone: a suntan-simulating agent. Arch Dermatol 82(4):505–507. https://doi.org/10.1001/archderm.1960.01580040023004
Manowitz M, Johnston VD (1967) Deposition of hexachlorophene on the skin. J Soc Cosmet Chem 18(8):527–536
Marples RR, Kligman AM (1974) Methods for evaluating topical antibacterial agents on human skin. Antimicrob Agents Chemother 5(3):323–329
Martin-Bouyer G, Lebreton R, Toga M, Stolley PD, Lockhart J (1982) Outbreak of accidental hexachlorophene poisoning in France. Lancet 1(8263):91–95. https://doi.org/10.1016/S0140-6736(82)90225-2
McNamara TF, Steinbach M (1967) In vitro evaluation of the tissue substantivity of selected antibacterial agents. J Am Oil Chem Soc 44(8):478–480. https://doi.org/10.1007/bf02908539
Menczel E, Maibach HI (1970) In vitro human percutaneous penetration of benzyl alcohol and testosterone: epidermal–dermal retention. J Investig Dermatol 54(5):386–394
Menkart J (1979) An analysis of adverse reactions to cosmetics. Cutis 24(6):599–662
Merchant S, Pathak V (1977) The role of barrier creams in cases of industrial dermatitis. Indian J Occup Health 20:45–47
Mertz PM, Alvarez OM, Smerbeck RV, Eaglstein WH (1984) A new in vivo model for the evaluation of topical antiseptics on superficial wounds. The effect of 70% alcohol and povidone-iodine solution. Arch Dermatol 120(1):58–62. https://doi.org/10.1001/archderm.1984.01650370064012
Monti D, Saettone MF, Centini M, Anselmi C (1993) Substantivity of sunscreens in vitro evaluation of the transdermal permeation characteristics of some benzophenone derivatives. Int J Cosmet Sci 15(2):45–52. https://doi.org/10.1111/j.1467-2494.1993.tb00068.x
Morasso MI, Thielemann AM, Pinto C, Figueroa M, Arancibia A (1985) In vitro and in vivo study of the substantivity of p-amino benzoic acid and two of its esters. J Soc Cosmet Chem 36:355–362
Morgan C, Renwick A, Friedmann P (2003) The role of stratum corneum and dermal microvascular perfusion in penetration and tissue levels of water-soluble drugs investigated by microdialysis. Br J Dermatol 148:434–443
Morohoshi K, Yamamoto H, Kamata R, Shiraishi F, Koda T, Morita M (2005) Estrogenic activity of 37 components of commercial sunscreen lotions evaluated by in vitro assays. Toxicol In Vitro 19:457–469
Murakami T, Yoshioka M, Okamoto I, Yumoto R, Higashi Y, Okahara K, Yata N (1998) Effect of ointment bases on topical and transdermal delivery of salicylic acid in rats: evaluation by skin microdialysis. J Pharm Pharmacol 50:55–61
Ngo MA, Maibach HI (2012) 15 Factors of percutaneous penetration of pesticides. In: Knaak JB, Timchalk C, Tornero-Velez R (eds) Parameters for pesticide QSAR and PBPK/PD models for human risk assessment. Oxford University Press, Danvers, pp 67–86
Reid DE, Walter CW, Buck AS (1950) Surgical scrubbing with pHisoderm G-11 as applied to a maternity hospital. Surg Gynecol Obstet 91(5):537–544
Ricci C, Pazzaglia M, Tosti A (1998) Photocontact dermatitis from UV filters. Contact Dermat 38(6):343–344. https://doi.org/10.1111/j.1600-0536.1998.tb05777.x
Saettone MF, Giannaccini B, Morganti C, Persi A, Cipriani C (1986) Substantivity of sunscreens: an appraisal of some quaternary ammonium sunscreens. Int J Cosmet Sci 8(1):9–25. https://doi.org/10.1111/j.1467-2494.1986.tb00426.x
Scheuplein RJ (1969) Mechanism of percutaneous adsorption. J Investig Dermatol 45:334
Schlumpf M, Cotton B, Conscience M, Haller V, Steinmann B, Lichtensteiger W (2001) In vitro and in vivo estrogenicity of UV screens. Environ Health Perspect 109:239–244
Schlumpf M, Schmid P, Durrer S, Conscience M, Maerkel K, Henseler M, Gruetter M, Herzog I, Reolon S, Ceccatelli R, Faass O, Stutz E, Jarry H, Wuttke W, Lichtensteiger W (2004) Endocrine activity and developmental toxicity of cosmetic UV filters—an update. Toxicology 205(1–2):113–122. https://doi.org/10.1016/j.tox.2004.06.043
Seidlova-Wuttke D, Christoffel J, Rimoldi G, Jarry H, Wuttke W (2006) Comparison of effects of estradiol with those of octylmethoxycinnamate and 4-methylbenzylidene camphor on fat tissue, lipids and pituitary hormones. Toxicol Appl Pharmacol 214:1–7
Seidlova-Wuttke D, Jarry H, Christoffel J, Rimoldi G, Wuttke W (2006) Comparison of effects of estradiol (E2) with those of octylmethoxycinnamate (OMC) and 4-methylbenzylidene camphor (4MBC)-2 filters of UV light—on several uterine, vaginal and bone parameters. Toxicol Appl Pharmacol 210:246–254
Shemano I, Nickerson M (1954) Cutaneous accumulation and retention of hexachlorophene-C14 (G-11). Fed Proc 13:404
Touitou E, Godin B (2006) New approaches for UV-induced photodamage protection. J Appl Cosmetol 24:139–147
Walling DW, Wujek SM, Levine F, Coleman-Nally DJ (1999) Transfer-resistant lip compositions. US 5,948,394
Ward WH, Lundgren HP (1954) The formation, composition, and properties of the keratins. Adv Protein Chem 9:243–297
Warshaw EM, Buchholz HJ, Belsito DV, Maibach HI, Fowler JF Jr, Rietschel RL, Zug KA, Mathias CG, Pratt MD, Sasseville D, Storrs FJ, Taylor JS, Deleo VA, Marks JG Jr (2009) Allergic patch test reactions associated with cosmetics: retrospective analysis of cross-sectional data from the North American Contact Dermatitis Group, 2001–2004. J Am Acad Dermatol 60(1):23–38. https://doi.org/10.1016/j.jaad.2008.07.056
Wester RC, Maibach HI (1983) Cutaneous pharmacokinetics: 10 steps to percutaneous absorption. Drug Metab Rev 14(2):169–205
Wester RC, Melendres J, Sedik L, Maibach H, Riviere JE (1998) Percutaneous absorption of salicylic acid, theophylline, 2, 4-dimethylamine, diethyl hexyl phthalic acid, and p-aminobenzoic acid in the isolated perfused porcine skin flap compared to man in vivo. Toxicol Appl Pharmacol 151(1):159–165. https://doi.org/10.1006/taap.1998.8434
Williams REO, Blowers R, Garrod LP, Shooter RA (1966) Hospital infections. Causes and prevention. Lloyd-Luke, London
Wurster DE, Dempski RE (1960) Adsorption of lipid-soluble substances by human keratin. J Am Pharm Assoc Am Pharm Assoc 49(5):305–307. https://doi.org/10.1002/jps.3030490513
Zhai H, Maibach HI (1996) Effect of barrier creams: human skin in vivo. Contact Dermat 35(2):92–96. https://doi.org/10.1111/j.1600-0536.1996.tb02297.x
Related articles recently published in Archives of Dermatological Research (selected by the journal’s editorial staff)
Alonso C, Marti M, Barba C, Carrer V, Rubio L, Coderch L (2017) Skin permeation and antioxidant efficacy of topically applied resveratrol. Arch Dermatol Res 309:423–431
Evans RL, Turner GA, Bates S, Robinson T, Arnold D, Marriott RE, Pudney PDA, Bonnist EYM, Green D (2017) Human axillary skin condition is improved following incorporation of glycerol into the stratum corneum from an antiperspirant formulation. Arch Dermatol Res 309:739–748
Li WH, Wong HK, Serrano J, Randhawa M, Kaur S, Southall MD, Parsa R (2017) Topical stabilized retinol treatment induces the expression of HAS genes and HA production in human skin in vitro and in vivo. Arch Dermatol Res 309:275–283
Sidgwick GP, McGeorge D, Bayat A (2016) Functional testing of topical skin formulations using an optimised ex vivo skin organ culture model. Arch Dermatol Res 308:297–308
Funding
No funding was received for this article.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
This article does not contain any studies with human participants or animals performed by any of the authors; therefore, informed consent is not applicable.
Rights and permissions
About this article
Cite this article
Li, B.S., Cary, J.H. & Maibach, H.I. Stratum corneum substantivity: drug development implications. Arch Dermatol Res 310, 537–549 (2018). https://doi.org/10.1007/s00403-018-1841-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00403-018-1841-9