A Data-Mining Approach for the Quantitative Assessment of Physicochemical Properties of Molecular Compounds in the Skin Flux

This paper aimed to provide an insight into the mechanism of transdermal penetration of drug molecules with respect to their physicochemical properties, such as solubility (S), the presence of enantiomer (ET) and logarithm of octanol–water partition coefficient (log P), molecular weight (MW), and melting point (MP). Propionic acid derivatives were evaluated for their flux through full-thickness skin excised from hairless mice upon being delivered from silicone-based pressure-sensitive adhesive (PSA) matrices in the presence or absence of various enhancers. The skin fluxes of model compounds were calculated based on the data obtained using the method engaged with the diffusion cell system. The statistical design of experiments (DoE) based on the factorial approach was used to find variables that have a significant impact on the outcomes. For the prediction of skin flux, a quantitative equation was derived using the data-mining approach on the relationship between skin permeation of model compounds (~125 mg/ml) and involved physicochemical variables. The most influential variables for the skin flux of propionic acid derivatives were the melting point (0.97) followed by the presence of enantiomer (0.95), molecular mass (0.93), log P values (0.86), and aqueous solubility (0.80). It was concluded that the skin flux of molecular compounds can be predicted based on the relationship between their physicochemical properties and the interaction with cofactors including additives and enhancers in the vehicles.

[1]  H. Maibach,et al.  Organic compounds percutaneous penetration in vivo in man: Relationship to mathematical predictive model. , 2020, Regulatory toxicology and pharmacology : RTP.

[2]  J. Renukuntla,et al.  Evaluation of Formulation Parameters on Permeation of Ibuprofen from Topical Formulations Using Strat-M® Membrane , 2020, Pharmaceutics.

[3]  Anne J Keurentjes,et al.  Percutaneous penetration of drugs applied in transdermal delivery systems: An in vivo based approach for evaluating computer generated penetration models. , 2019, Regulatory toxicology and pharmacology : RTP.

[4]  H. Wörner,et al.  Real-time probing of chirality during a chemical reaction , 2019, Proceedings of the National Academy of Sciences.

[5]  Karl Leo,et al.  Impact of molecular quadrupole moments on the energy levels at organic heterojunctions , 2019, Nature Communications.

[6]  M. Wilkins,et al.  Differential Ion Mobility-Mass Spectrometry for Detailed Analysis of the Proteome. , 2019, Trends in biotechnology.

[7]  S. Takata,et al.  Evaluation of anionic surfactants effects on the skin barrier function based on skin permeability , 2019, Pharmaceutical development and technology.

[8]  P. Quan,et al.  The role of carboxyl group of pressure sensitive adhesive in controlled release of propranolol in transdermal patch: Quantitative determination of ionic interaction and molecular mechanism characterization , 2018, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[9]  H. Drexler,et al.  Evaluation on the reliability of the permeability coefficient (Kp) to assess the percutaneous penetration property of chemicals on the basis of Flynn’s dataset , 2018, International Archives of Occupational and Environmental Health.

[10]  D. Haddleton,et al.  Transdermal Delivery of Ibuprofen Utilizing a Novel Solvent-Free Pressure-sensitive Adhesive (PSA): TEPI® Technology , 2017, Journal of Pharmaceutical Innovation.

[11]  Chi H. Lee,et al.  Augmented reality for personalized nanomedicines. , 2017, Biotechnology advances.

[12]  Gregory W. Kauffman,et al.  Assessing Physicochemical Properties of Drug Molecules via Microsolvation Measurements with Differential Mobility Spectrometry , 2017, ACS central science.

[13]  J. Hadgraft,et al.  Advanced topical formulations (ATF). , 2016, International journal of pharmaceutics.

[14]  T. Phaechamud,et al.  Evaporation Behavior and Characterization of Eutectic Solvent and Ibuprofen Eutectic Solution , 2016, AAPS PharmSciTech.

[15]  Ljiljana Djekic,et al.  Formulation of hydrogel-thickened nonionic microemulsions with enhanced percutaneous delivery of ibuprofen assessed in vivo in rats. , 2016, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[16]  Huibiao Liu,et al.  A method for controlling the synthesis of stable twisted two-dimensional conjugated molecules , 2016, Nature Communications.

[17]  W. S. Hopkins,et al.  Using differential mobility spectrometry to measure ion solvation: an examination of the roles of solvents and ionic structures in separating quinoline-based drugs. , 2015, The Analyst.

[18]  Yugyung Lee,et al.  A cascade computer model for mocrobicide diffusivity from mucoadhesive formulations , 2015, BMC Bioinformatics.

[19]  Kim Ekroos,et al.  Differential mobility spectrometry-driven shotgun lipidomics. , 2014, Analytical chemistry.

[20]  R. Langer,et al.  Skin permeabilization for transdermal drug delivery: recent advances and future prospects , 2014, Expert opinion on drug delivery.

[21]  H. Derendorf,et al.  Importance of Relating Efficacy Measures to Unbound Drug Concentrations for Anti-Infective Agents , 2013, Clinical Microbiology Reviews.

[22]  Chi H. Lee,et al.  Computational analysis and predictive modeling of polymorph descriptors , 2013, Chemistry Central Journal.

[23]  J. Campbell,et al.  Probing electrospray ionization dynamics using differential mobility spectrometry: the curious case of 4-aminobenzoic acid. , 2012, Analytical chemistry.

[24]  A. Stinchcomb,et al.  Estimation of maximum transdermal flux of nonionized xenobiotics from basic physicochemical determinants. , 2012, Molecular pharmaceutics.

[25]  T. Phaechamud,et al.  Menthol, Borneol, Camphor and WS-3 Eutectic Mixture , 2012 .

[26]  Hiroaki Todo,et al.  Influence of skin thickness on the in vitro permeabilities of drugs through Sprague-Dawley rat or Yucatan micropig skin. , 2012, Biological & pharmaceutical bulletin.

[27]  S. K. Li,et al.  Structure Enhancement Relationship of Chemical Penetration Enhancers in Drug Transport across the Stratum Corneum , 2012, Pharmaceutics.

[28]  E. Bertin,et al.  The influence of flux balance on the generalized chemical potential in mass transport models , 2011, 1106.5652.

[29]  A. Goodman JCGS@20, Visuals@40, Interface@45 & !!Challenges!! , 2011 .

[30]  K. Bauerová,et al.  Does stereochemistry influence transdermal permeation of flurbiprofen through the rat skin? , 2010, Archives of Dermatological Research.

[31]  Hoo-Kyun Choi,et al.  Recent advances in transdermal drug delivery , 2010, Archives of pharmacal research.

[32]  Chun-Jen Yang,et al.  Construction of a quantitative structure-permeability relationship (QSPR) for the transdermal delivery of NSAIDs. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[33]  Michael S. Roberts,et al.  Skin Solubility Determines Maximum Transepidermal Flux for Similar Size Molecules , 2009, Pharmaceutical Research.

[34]  S. K. Li,et al.  Comparison of the effects of chemical permeation enhancers on the lipoidal pathways of human epidermal membrane and hairless mouse skin and the mechanism of enhancer action. , 2007, Journal of pharmaceutical sciences.

[35]  J. Breytenbach,et al.  Synthesis and transdermal penetration of NSAID glycoside esters. , 2005, International journal of pharmaceutics.

[36]  N. He,et al.  Mechanistic study of chemical skin permeation enhancers with different polar and lipophilic functional groups. , 2004, Journal of pharmaceutical sciences.

[37]  Scott C. Wasdo,et al.  Designing for topical delivery: Prodrugs can make the difference , 2003, Medicinal research reviews.

[38]  Adrian C. Williams,et al.  Transdermal and Topical Drug Delivery : From Theory to Clinical Practice , 2003 .

[39]  Hoo-Kyun Choi,et al.  Effects of Vehicles and Pressure Sensitive Adhesives on the Penetration of Isosorbide Dinitrate Across the Hairless Mouse Skin , 2002, Drug delivery.

[40]  B. W. Barry,et al.  Novel mechanisms and devices to enable successful transdermal drug delivery. , 2001, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[41]  Luiz Paulo Fávero,et al.  Design and Analysis of Experiments , 2001, Handbook of statistics.

[42]  R. Guy,et al.  PERCUTANEOUS PENETRATION ENHANCEMENT: PHYSICOCHEMICAL CONSIDERATIONS AND IMPLICATIONS FOR PRODRUG DESIGN* , 2001 .

[43]  J. Hadgraft,et al.  The selection of non-steroidal anti-inflammatory agents for dermal delivery. , 2000, International journal of pharmaceutics.

[44]  C. Goosen,et al.  The influence of the physicochemical characteristics and pharmacokinetic properties of selected NSAID's on their transdermal absorption. , 2000, International journal of pharmaceutics.

[45]  Hoo-Kyun Choi,et al.  Enhancement of percutaneous absorption of ketoprofen: effect of vehicles and adhesive matrix , 1998 .

[46]  C. Goosen,et al.  Correlation between physicochemical characteristics, pharmacokinetic properties and transdermal absorption of NSAID's , 1998 .

[47]  Michael S. Roberts,et al.  Epidermal permeability — Penetrant structure relationships: 3. The effect of hydrogen bonding interactions and molecular size on diffusion across the stratum corneum , 1996 .

[48]  Hoo-Kyun Choi,et al.  Mathematical Analysis and Optimization of a Flow-Through Diffusion Cell System , 1994, Pharmaceutical Research.

[49]  M. Haga,et al.  Enantiomeric difference in percutaneous penetration of propranolol through rat excised skin. , 1992, Chemical & pharmaceutical bulletin.

[50]  B. Bloom,et al.  NSAID dosing schedule and compliance , 1988, Drug intelligence & clinical pharmacy.

[51]  Brian W. Barry,et al.  Mode of action of penetration enhancers in human skin , 1987 .

[52]  T Yano,et al.  Skin permeability of various non-steroidal anti-inflammatory drugs in man. , 1986, Life sciences.

[53]  Jonathan Hadgraft,et al.  Transdermal drug delivery: a simplified pharmacokinetic approach , 1985 .

[54]  M. Angamuthu,et al.  Role of Physical, Chemical Percutaneous Penetration Enhancement Methods: A Concise Review , 2017 .

[55]  Susan Budavari,et al.  The Merck index : an encyclopedia of chemicals, drugs, and biologicals , 2001 .

[56]  J. Berba,et al.  In vitro release of selected nonsteroidal antiinflammatory analgesics [NSAIA] from reservoir-type transdermal formulations , 1991 .

[57]  H. Abdou Dissolution, Bioavailability and Bioequivalence , 1990 .

[58]  G. Isaia,et al.  Anesthetic Pharmacology International Society for Anaesthetic Pharmacology Dexibuprofen (s(؉)-isomer Ibuprofen) Reduces Gastric Damage and Improves Analgesic and Antiinflammatory Effects in Rodents , 2022 .

[59]  Molecular Pharmaceutics & Organic Process Research Role of Surfactants as Penetration Enhancer in Transdermal Drug Delivery System , 2022 .