Suitability of lipophilic and hydrophilic artificial membranes for the evaluation of in vitro methyl p-hydroxybenzoate penetration

Dorota Piwowarczyk, Anna Nowak, Adam Klimowicz


Introduction: Parabens are the group of the most frequently applied preservatives in cosmetics as well as topical therapeutics. From the chemical point of view they are the esters of p-hydroxybenzoic acid. Their popularity is due to their broad spectrum of antimicrobial activity, applicability in a wide pH range, as well as low production costs. Despite the controversy regarding the safety of their use, parabens seem to be recognized as non-toxic and low allergenic agents.

The aim of the study was to determine paraben M (methyl-4-hydroxybenzoate) penetration through the hydrophilic and lipophilic artificial membranes.

Materials and methods: Paraben M penetration into acceptor fluid of pH 5.4, comparable to skin surface pH, as well as into that of pH 7.4, corresponding to the deeper skin layers, was evaluated with Franz diffusion cells. The samples of acceptor fluid were collected after 0.5, 1, 2 and 4 hours, and paraben M concentrations were determined by the HPLC method.

Results: The results of the studies suggest the ability of paraben M to penetrate through both tested artificial membranes. The compound penetrated to a higher degree after 0.5% cream application as compared to 0.5% gel, regardless of the character of the membrane. Moreover, paraben M had a higher penetration into acceptor fluid of pH 7.4 as compared to that of pH 5.4.

Conclusion: Membrane character, i.e. hydrophilic or lipophilic, seems not to have an impact on paraben M penetration. However, the form of the product (i.e. gel vs. cream) affects its permeation. The lower penetration of the studied compound into acceptor fluid of pH 5.4 could suggest the possibility of certain increase of the epidermal barrier effectiveness.


parabens; permeation; preservatives; cosmetic vehicle

Full Text:

PDF (Język Polski)


Lane ME. Skin penetration enhancers. Int J Pharm 2013;447(1-2):12-21. doi: 10.1016/j.ijpharm.2013.02.040.

Hadgraft J. Skin deep. J Eur Pharm Biopharm 2004;58(2):291-9. doi: 10.1016/j.ejpb.2004.03.002.

Trommer H, Neubert RH. Overcoming the stratum corneum: The modulation of skin penetration. Skin Pharmacol Physiol 2006;19(2):106-21. doi: 10.1159/000091978.

Lam PL, Gambari R. Advanced progress of microencapsulation technologies: in vivo and in vitro models for studying oral and transdermal drug deliveries. J Control Release 2014;178:25-45.

Bolzinger MA, Briancon S, Pelletier J, Chevalier Y. Penetration of drug through skin, a complex rate-controlling membrane. Curr Opin Colloid Interface Sci 2012;17:156-65.

Baroni A, Buommino E, De Gregorio V, Ruocco E, Ruocco V, Wolf R. Structure and function of the epidermis related to carrier properties. Clin Dermatol 2012;30(3):257-62. doi: 10.1016/j.clindermatol.2011.08.007.

Prausnitz MR, Langer R. Transdermal drug deliviery. Nat Biotechnol 2008;26(11):1261-68. doi: 10.1038/nbt.1504.

Meuwissen ME, Janssen J, Cullander C, Junginger HE, Bouwstra JA. A cross-section device to improve visualization of fluorescent probe penetration into the skin by confocal laser scanning microscopy. Pharm Res 1998;15:352-6.

Waters LJ, Dennis L, Bibi A, Mitchell JC. Surfactant and temperature effects on paraben transport through silicone membranes. Colloids Surf B Biointerfaces 2013;108:23-8. doi: 10.1016/j.colsurfb.2013.02.017.

Dias M, Hadgraft J, Lane ME. Influence of membrane-solvent-solute interactions on solute permeation in model membranes. Int J Pharm 2007;336(1):108-14. doi: 10.1016/j.ijpharm.2006.11.054.

Balázs B, Vizserálek G, Berkó S, Budai-Szűcs B, Keleman A, Sinkó B, et al. Investigation of the efficacy of transdermal penetration enhancers through the use of human skin and a skin mimic artificial membrane. J Pharm Sci 2016;105(3):1134-40. doi: 10.1016/S0022-3549(15)00172-0.

Karadzovska D, Riviere JE. Assessing vehicle effect on skin absorption using artificial membrane assays. Eur J Pharm Sci 2013;50(5):569-76. doi: 10.1016/j.ejps.2013.02.020.

Tsinman K, Sinko B. A high throughput method to predict skin penetration and screen topical formulations. Cosmet Toiletries 2013;128:192-9.

Sinkó B, Garrigues TM, Balogh GT, Nagy ZK, Tsinman O, Avdeef A, et al. Skin-PAMPA: A new method for fast prediction of skin penetration. Eur J Pharm Sci 2012;45(5):698-707. doi: 10.1016/j.ejps.2012.01.011.

Palac Z, Engesland A, Flaten GE, Škalko-Basnet N, Filipović-Grčić J, Vanić Ž. Liposomes for (trans)dermal drug delivery: the skin-PVPA as a novel in vitro stratum corneum model in formulation development. J Liposome Res 2014;24:313-22.

Engesland A, Skar M, Hansen T, Škalko-Basnet N, Flaten GE. New application of phospholipid vesicle-based permeation assay: permeation model mimicking skin barrier. J Pharm Sci 2013;102(5):1588-600. doi: 10.1002/jps.23509.

Engesland A, Škalko-Basnet N, Flaten GE. Phospholipid vesicle-based permeation assay and Episkin® in assessment of drug therapies destined for skin administration. J Pharm Sci 2015;104(3):1119-27. doi: 10.1002/jps.24315.

Loftsson T, Konrádsdóttir F, Másson M. Development and evaluation of an artificial membrane for determination of drug availability. Int J Pharm 2006;326:60-8. doi: 10.1016/j.ijpharm.2006.07.009.

Pedersen S, Marra E, Nicoli S, Santi P. In vitro skin permeation and retention of parabens from cosmetic formulations. Int J Cosmet Sci 2007;29(5):361-7. doi: 10.1111/j.1468-2494.2007.00388.x.

Jaworska M, Sikora E, Ogonowski J. Czynniki wpływające na penetrację składników aktywnych przez skórę. Wiad Chem 2011;65:301-20.

Gruvberger B, Bruze M, Tammela M. Preservatives in moisturizers on the Swedish market. Acta Derm Venereol 1998:78(1);52-6.

Bojarowicz H, Wojciechowska M, Gocki J. Substancje konserwujące stosowane w kosmetykach oraz ich działanie niepożądane. Probl Hig Epidemiol 2008;89:30-3.

Nishida K, Kobayashi M, Miyamoto H, Yoshikawa N, Fumoto S, Sasaki H, et al. Relationship between lipophilicity and absorption from the liver surface of paraben derivatives and antipyrine in rats. J Pharm Pharmacol 2011;63(5):736-40. doi: 10.1111/j.2042-7158.2011.01276.x.

Caon T, Costa AC, de Oliviera MA, Micke GA, Simoes CM. Evaluation of transdermal permeation of different paraben combinations through a pig ear skin model. Int J Pharm 2010;391(1-2):1-6. doi: 10.1016/j.ijpharm.2010.02.006.

Bouwstra JA, Ponec M. The skin barrier in healthy and diseased state. Biochim Biophys Acta 2006;1758(12):2080-95. doi: 10.1016/j.bbamem.2006.06.021.

Di Cango M, Bibi HA, Bauer-Brandl A. New biomimetic barrier ParmeapadTM for efficient investigation of passive permeability of drugs. Eur J Pharm Sci 2015;73:29-34. doi: 10.1016/j.ejps.2015.03.019.

Seki T, Mochida J, Okamoto M, Hosoya O, Juni K, Morimoto K. Measurement of diffusion coefficients of parabens and steroids in water and 1-octanol. Chem Pharm Bull (Tokyo) 2003;51(6):734-6.

El Hussein S, Muret P, Berard M, Makki S, Humbert P. Assessment of principal parabens used in cosmetics after their passage through human epidermis-dermis layers (ex-vivo study). Exp Dermatol 2007;16(10):830-6. doi: 10.1111/j.1600-0625.2007.00625.x.

Cross SE, Roberts MS. The effect of occlusion on epidermal penetration of parabens from a commercial allergy test ointment, acetone and ethanol vehicles. J Invest Dermatol 2000;115(5):914-8. doi: 10.1046/j.1523-1747.2000.00151.x.

Arct J, Oborska A, Mojski M, Chudzicki M. Proper selection of cosmetic ingredients as a key factor in skin penetration of flavonoids – in vivo studies. Pol J Cosmetol 2016;19:59-63.

Stahl J, Wohlert M, Kietzmann M. The effect of formulation vehicles on the in vitro percutaneous permeation of ibuprofen. BMC Pharmacol 2011;11:12. doi: 10.1186/1471-2210-11-12.


Copyright (c) 2017 Dorota Piwowarczyk, Anna Nowak, Adam Klimowicz

License URL: