Screening of Chemical Penetration Enhancers for Transdermal Drug Delivery Using Electrical Resistance of Skin

PurposeA novel technique is presented for identifying potential chemical penetration enhancers (CPEs) based on changes in the electrical resistance of skin.MethodsSpecifically, a multi-well resistance chamber was designed and constructed to facilitate more rapid determination of the effect of CPEs on skin resistance. The experimental setup was validated using nicotine and decanol on porcine skin in vitro. The multi-well resistance chambers were capable of operating at 37°C in order to simulate the physiological temperature of the human body. Further, the utility of the multi-well resistance chamber technique was validated using standard Franz diffusion cells. Electrical resistance measurements were used to evaluate the potency of seven new potential CPEs, identified using virtual screening algorithms. From the resistance measurements, the chemicals 1-dodecyl-2-pyrrolidinone (P), menthone (M) and R(+)-3-amino-1-hydroxy-2-pyrrolidinone (C) were identified as the better penetration enhancers among the seven tested. Further, traditional permeation experiments were performed in Franz diffusion cells to confirm our findings.ResultsThe permeation test results indicated that, of the three CPEs deemed potentially viable using the newly-developed resistance screening technique, both P and M increased the permeation of the test drug (melatonin) through skin in 48 h.ConclusionIn summary, this resistance technique can be used to effectively pre-evaluate potential CPEs, thereby reducing the time required to conduct the permeability studies.

[1]  K. Knutson,et al.  Enhanced permeation of polar compounds through human epidermis. I. Permeability and membrane structural changes in the presence of short chain alcohols. , 1994, Biochimica et biophysica acta.

[2]  T. Nagai,et al.  Combined effect of d-limonene pretreatment and temperature on the rat skin permeation of lipophilic and hydrophilic drugs. , 1995, Biological & pharmaceutical bulletin.

[3]  Y. Chien,et al.  Biomembrane permeation of nicotine: mechanistic studies with porcine mucosae and skin. , 1997, Journal of pharmaceutical sciences.

[4]  S W Hui,et al.  Characterization of electric-pulse-induced permeabilization of porcine skin using surface electrodes. , 1997, Biophysical journal.

[5]  M Liebsch,et al.  The ECVAM International Validation Study on In Vitro Tests for Skin Corrosivity. 2. Results and Evaluation by the Management Team. , 1998, Toxicology in vitro : an international journal published in association with BIBRA.

[6]  M. Singh,et al.  Effect of Fatty acids on the Permeation of Melatonin across Rat and Pig Skin In‐vitro and on the Transepidermal Water Loss in Rats In‐vivo , 1999, The Journal of pharmacy and pharmacology.

[7]  S. Mitragotri,et al.  Synergistic effect of low-frequency ultrasound and sodium lauryl sulfate on transdermal transport. , 2000, Journal of pharmaceutical sciences.

[8]  Y. Oh,et al.  Effects of vehicles and enhancers on transdermal delivery of melatonin. , 2001, International journal of pharmaceutics.

[9]  R. B. Walker,et al.  The effect of variations in pH and temperature on stability of melatonin in aqueous solution , 2001, Journal of pineal research.

[10]  J. Heylings,et al.  Comparison of tissue sources for the skin integrity function test (SIFT). , 2001, Toxicology in vitro : an international journal published in association with BIBRA.

[11]  M. Singh,et al.  Comparison of the effect of fatty alcohols on the permeation of melatonin between porcine and human skin. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[12]  Mandip Singh,et al.  Effect of vehicles on the transdermal delivery of melatonin across porcine skin in vitro. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[13]  M. Mumtaz,et al.  Effect of chemical interactions in pentachlorophenol mixtures on skin and membrane transport. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[14]  O. Corrigan,et al.  Iontophoretic and chemical enhancement of drug delivery. Part I: across artificial membranes. , 2003, International journal of pharmaceutics.

[15]  Samir Mitragotri,et al.  Discovery of transdermal penetration enhancers by high-throughput screening , 2004, Nature Biotechnology.

[16]  J. Heylings,et al.  Multi-species assessment of electrical resistance as a skin integrity marker for in vitro percutaneous absorption studies. , 2004, Toxicology in vitro : an international journal published in association with BIBRA.

[17]  Adrian C. Williams,et al.  Penetration enhancers. , 2004, Advanced drug delivery reviews.

[18]  Samir Mitragotri,et al.  Dependence of Skin Permeability on Contact Area , 2003, Pharmaceutical Research.

[19]  Samir Mitragotri,et al.  High Throughput Screening of Transdermal Formulations , 2002, Pharmaceutical Research.

[20]  P. Hinderliter,et al.  The Tinsley LCR Databridge Model 6401 and electrical impedance measurements to evaluate skin integrity in vitro. , 2004, Toxicology in vitro : an international journal published in association with BIBRA.

[21]  Igor V. Tetko,et al.  Virtual Computational Chemistry Laboratory – Design and Description , 2005, J. Comput. Aided Mol. Des..

[22]  R. L. Robinson,et al.  SVRC–QSPR model for predicting saturated vapor pressures of pure fluids , 2006 .

[23]  S. Mitragotri,et al.  Evaluation of chemical enhancers in the transdermal delivery of lidocaine. , 2006, International journal of pharmaceutics.

[24]  K. Gasem,et al.  An Improved Structure−Property Model for Predicting Melting-Point Temperatures , 2006 .

[25]  S. Mitragotri,et al.  Relationships between skin's electrical impedance and permeability in the presence of chemical enhancers. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[26]  A. Urtti,et al.  Rat epidermal keratinocyte organotypic culture (ROC) compared to human cadaver skin: the effect of skin permeation enhancers. , 2007, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[27]  R. L. Robinson,et al.  QSPR generalization of activity coefficient models for predicting vapor–liquid equilibrium behavior , 2007 .