Validation of an In vitro-in vivo Assay System for Evaluation of Transdermal Delivery of Caffeine

Author(s): Fanni Farner, Luca Bors, Ágnes Bajza, Gellért Karvaly, István Antal, Franciska Erdő*.

Journal Name: Drug Delivery Letters

Volume 9 , Issue 1 , 2019

Submit Manuscript
Submit Proposal

Graphical Abstract:


Introduction: Degree of skin penetration of topical drugs and cosmetics is a crucial point concerning their effects and tolerability. For testing drug delivery across the dermal barrier different in vitro and in vivo assays have been developed. Caffeine has been shown to have beneficial effects against skin aging, sunburn and hair-loss, and it is protective against melanoma and non-melanoma type skin cancers. Aim of our study was to set up an assay system to evaluate caffeine penetration from topical formulation into the skin.

Methods: Franz diffusion cells consisting of either a filter paper or an artificial membrane or rat skin were used as in vitro/ex vivo test systems and transdermal microdialysis in anaesthetized rats was performed as an in vivo assay.

Results: Results indicate that Franz diffusion cell studies provide a good approximation of the release of caffeine from the formulation but are not able to differentiate between 2% and 4% cream concentrations. The maximum concentrations (Cmax) in case of the 2% cream formulation were 708.3 (2.7 μm pore), 78.7 (0.8 µm pore), 45.3 (0.45 µm pore) and 44.9 (rat skin) µg/7.5 mL, respectively. The in vivo microdialysis experiments were in accordance with the in vitro and ex vivo results and gave more information on the dynamics and follicular and transcellular phases of drug penetration through the layers of the skin.

Discussion and Conclusion: Taken together, Franz diffusion cell and transdermal microdialysis are a good combination to evaluate caffeine release and penetration into the skin from the formulations tested. This system might also be used for rapid testing of other hydrophilic topical drugs and has a benefit in the prediction for human skin absorption and tolerability studies, in an early phase of drug development.

Keywords: Transdermal microdialysis, Franz diffusion cell, skin penetration, caffeine, in vivo-in vitro correlation, dermal barrier.

Metro, D.; Cernaro, V.; Santoro, D.; Papa, M.; Buemi, M.; Benvenga, S.; Manasseri, L. Beneficial effects of oral pure caffeine on oxidative stress. J. Clin. Transl. Endocrinol., 2017, 10, 22-27.
Herman, A.; Herman, A.P. Caffeine’s mechanisms of action and its cosmetic use. Skin Pharmacol. Physiol., 2013, 26, 8-14.
Kerzendorfer, C.; O’Driscoll, M. UVB and caffeine: Inhibiting the DNA damage response to protect against the adverse effects of UVB. J. Invest. Dermatol., 2009, 129, 1611-1613.
Wu, S.; Han, J.; Song, F.; Cho, E.; Gao, X.; Hunter, D.J.; Qureshi, A.A. Caffeine intake, coffee consumption, and risk of cutaneous malignant melanoma. Epidemiology, 2015, 26, 898-908.
Conney, A.H.; Lu, Y.P.; Lou, Y.R.; Huang, M.T. Inhibitory effects of tea and caffeine on UV-induced carcinogenesis: relationship to enhanced apoptosis and decreased tissue fat. Eur. J. Cancer Prev., 2002, 11, 28-36.
Loftfield, E.; Freedman, N.D.; Graubard, B.I.; Hollenbeck, A.R.; Shebl, F.M.; Mayne, S.T.; Sinha, R. Coffee drinking and cutaneous melanoma risk in the NIH-AARP diet and health study. J. Natl. Cancer Inst., 2015, 107, 1-9.
Bors, L.; Bajza, Á.; Kocsis, D.; Erdő, F. Caffeine: Traditional and new therapeutic indications and use as a dermatological model drug -A review. Orv. Hetil., 2018, 159(10), 384-390.
Liu, D.; Zhang, C.; Zhang, X.; Zhen, Z.; Wang, P.; Li, J.; Yi, D.; Jin, Y.; Yang, D. Permeation measurement of gestodene for some biodegradable materials using Franz diffusion cells. Saudi Pharm. J., 2015, 23, 413-420.
Kshirsagar, S.J.; Bhalekar, M.R.; Mohapatra, S.K. Development and evaluation of carvedilol-loaded transdermal drug delivery system: In-vitro and in-vivo characterization study. Drug Dev. Ind. Pharm., 2012, 38(12), 1530-1537.
Rauma, M.; Johanson, G. Comparison of the thermogravimetric analysis (TGA) and Franz cell methods to assess dermal diffusion of volatile chemicals. Toxicol. In Vitro, 2009, 23(5), 919-926.
Espinal-Ruiz, M.; Restrepo-Sánchez, L.P.; Narváez-Cuenca, C.E. Effect of pectins on the mass transfer kinetics of monosaccharides, amino acids, and a corn oil-in-water emulsion in a Franz diffusion cell. Food Chem., 2016, 209, 144-153.
Vithlani, S.; Sarraf, S.; Chaw, C.S. Formulation and In vitro evaluation of self-emulsifying formulations of Cinnarizine. Drug Dev. Ind. Pharm., 2012, 38(10), 1188-1194.
Boateng, J.S.; Matthews, K.H.; Auffret, A.D.; Humphrey, M.J.; Eccleston, G.M.; Stevens, H.N. Comparison of the In vitro release characteristics of mucosal freeze-dried wafers and solvent-cast films containing an insoluble drug. Drug Dev. Ind. Pharm., 2012, 38(1), 47-54.
Gao, X.; Chen, L.; Xie, J.; Yin, Y.; Chang, T.; Duan, Y.; Jiang, N. In vitro controlled release of vitamin C from Ca/Al layered double hydroxide drug delivery system. Mater. Sci. Eng., 2014, 39, 56-60.
Zare, M.; Mobedi, H.; Barzin, J.; Mivehchi, H.; Jamshidi, A.; Mashayekhi, R. Effect of additives on release profile of leuprolide acetate in an in situ forming controlled-release system: In vitro study. J. Appl. Polym. Sci., 2008, 107, 3781-3787.
Baert, B.; Vansteelandt, S.; De Spiegeleer, B. Ion mobility spectrometry as a high-throughput technique for in vitro transdermal Franz diffusion cell experiments of ibuprofen. J. Pharm. Biomed. Anal., 2011, 55(3), 472-478.
Baert, B.; De Spiegeleer, B. Local skin pharmacokinetics of talarozole, a new retinoic acid metabolism-blocking agent. Skin Pharmacol. Physiol., 2011, 24(3), 151-159.
Jung, Y.; Yoon, J.H.; Kang, N.; Park, S.; Jeong, S. Diffusion properties of different compounds across various synthetic membranes using Franz-type diffusion cells. J. Pharm. Investig., 2012, 42, 271-277.
Ng, S.F.; Rouse, J.; Sanderson, F.; Eccleston, G. The relevance of polymeric synthetic membranes in topical formulation assessment and drug diffusion study. Arch. Pharm. Res., 2012, 35, 579-593.
Erdő, F.; Hashimoto, N.; Karvaly, G.; Nakamichi, N.; Kato, Y. Critical evaluation and methodological positioning of the transdermal microdialysis technique. A review. J. Control. Release, 2016, 233, 147-161.
Otberg, N.; Patzelt, A.; Rasulev, U.; Hagemeister, T.; Linscheid, M.; Sinkgraven, R.; Sterry, W.; Lademann, J. The role of hair follicles in the percutaneous absorption of caffeine. Br. J. Clin. Pharmacol., 2008, 65(4), 488-492.
Otberg, N.; Teichmann, A.; Rasuljev, U.; Sinkgraven, R.; Sterry, W.; Lademann, J. Follicular penetration of topically applied caffeine via a shampoo formulation. Skin Pharmacol. Physiol., 2007, 20(4), 195-198.
Alberti, M.; Dancik, Y.; Sriram, G.; Wu, B.; Teo, Y.L.; Feng, Z.; Bigliardi-Qi, M.; Wu, R.G.; Wang, Z.P.; Bigliardi, P.L. Multi-chamber microfluidic platform for high-precision skin permeation testing. Lab Chip, 2017, 17(9), 1625-1634.
Beißner, N.; Bolea Albero, A.; Füller, J.; Kellner, T.; Lauterboeck, L.; Liang, J.; Böl, M.; Glasmacher, B.; Müller-Goymann, C.C.; Reichl, S. Improved in vitro models for preclinical drug and formulation screening focusing on 2D and 3D skin and cornea constructs. Eur. J. Pharm. Biopharm., 2018, 126, 57-66.
Mattern, K.; Beißner, N.; Reichl, S.; Dietzel, A. DynaMiTES - A dynamic cell culture platform for in vitro drug testing PART 1 - Engineering of microfluidic system and technical simulations. Eur. J. Pharm. Biopharm., 2018, 126, 159-165.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [15 - 20]
Pages: 6
DOI: 10.2174/2210303108666180903102107

Article Metrics

PDF: 28