445
Views
14
CrossRef citations to date
0
Altmetric
Review

Modeling percutaneous absorption for successful drug discovery and development

ORCID Icon, , &
Pages 1181-1198 | Received 25 Oct 2019, Accepted 08 Jun 2020, Published online: 25 Jun 2020

References

  • Pastore MN, Kalia YN, Horstmann M, et al., Transdermal patches: history, development and pharmacology. Br J Pharmacol. 2015:172(9):2179–2209.
  • Topical drug delivery market to reach $123bn by 2024. Outsourcing-pharma.com. England: William Reed Business Media Ltd; 2019 [Accessed 2020 May 14]. Available from: https://www.outsourcing-pharma.com/Article/2019/08/21/Projected-growth-for-the-topical-drug-delivery-market?utm_source=copyright&utm_medium=OnSite&utm_campaign=copyright
  • Dickson M, Gagnon JP. Key factors in the rising cost of new drug discovery and development. Nat Rev Drug Discov. 2004;3(5):417–429.
  • Orange book: approved drug products with therapeutic equivalence evaluations. U.S. Department of Health and Human Services. Silver Spring, MD: U.S. Food and Drug Administration. [Accessed 2020 May 21]. Available from: https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm
  • Khan PM, Roy K. Current approaches for choosing feature selection and learning algorithms in quantitative structure–activity relationships (QSAR). Expert Opin Drug Discov. 2018;13(12):1075–1089.
  • Osborne L. Certara partners with galderma to attain FDA approval of AKLIEF® topical acne cream. United States, NJ: Certara; 2020 [Accessed 2020 May 13]. Available from: https://www.certara.com/pressreleases/certara-partners-with-galderma-in-advancing-modeling-and-simulation-technology-to-attain-fda-approval-of-aklief-topical-acne-cream/
  • Chetty M, Johnson TN, Polak S, et al. Physiologically based pharmacokinetic modelling to guide drug delivery in older people. Adv Drug Del Rev. 2018;135:85–96.
  • PubChem database. [ Accessed 2020 May 21]. Available from: https://pubchem.ncbi.nlm.nih.gov/
  • ChemSpider database. [ Accessed 2020 May 21]. Available from: https://www.chemspider.com/
  • Drugbank database (version 5.1.6). [ Accessed 2020 May 21]. Available from: https://www.drugbank.ca/
  • Chemical Book. [ Accessed 2020 May 21]. Available from: https://www.chemicalbook.com/
  • Touitou E. Drug delivery across the skin. Expert Opin Biol Ther. 2002;2(7):723–733.
  • Anissimov YG, Jepps OG, Dancik Y, et al., Mathematical and pharmacokinetic modelling of epidermal and dermal transport processes. Adv Drug Del Rev. 2013:65(2):169–190.
  • Barry B. Modern methods of promoting drug absorption through the skin. Mol Aspects Med. 1991;12(3):195–241.
  • Mitragotri S, Anissimov YG, Bunge AL, et al., Mathematical models of skin permeability: an overview. Int J Pharm. 2011:418(1):115–129.
  • Frum Y, Bonner MC, Eccleston GM, et al. The influence of drug partition coefficient on follicular penetration: in vitro human skin studies. Eur J Pharm Sci. 2007;30(3–4):280–287.
  • Liu X, Grice JE, Lademann J, et al., Hair follicles contribute significantly to penetration through human skin only at times soon after application as a solvent deposited solid in man. Br J Clin Pharmacol. 2011:72(5):768–774.
  • Grice JE, Ciotti S, Weiner N, et al. Relative uptake of minoxidil into appendages and stratum corneum and permeation through human skin in vitro. J Pharm Sci. 2010;99(2):712–718.
  • Scheuplein RJ. Mechanism of percutaneous absorption: II. Transient diffusion and the relative importance of various routes of skin penetration. J Invest Dermatol. 1967;48(1):79–88.
  • Roberts M, Mohammed Y, Pastore M, et al. Topical and cutaneous delivery using nanosystems. J Control Release. 2017;247:86–105.
  • Dancik Y, Anissimov YG, Jepps OG, et al., Convective transport of highly plasma protein bound drugs facilitates direct penetration into deep tissues after topical application. Br J Clin Pharmacol. 2012:73(4):564–578.
  • Baba H, Ueno Y, Hashida M, et al. Quantitative prediction of ionization effect on human skin permeability. Int J Pharm. 2017;522(1–2):222–233.
  • Mudry B, Carrupt P-A, Guy RH, et al. Quantitative structure–permeation relationship for iontophoretic transport across the skin. J Control Release. 2007;122(2):165–172.
  • Roberts MS, Cross S, Anissimov Y. Factors affecting the formation of a skin reservoir for topically applied solutes. Skin Pharmacol Physiol. 2004;17(1):3–16.
  • Zhang Q, Grice JE, Li P, et al., Skin solubility determines maximum transepidermal flux for similar size molecules. Pharm Res. 2009:26(8):1974–1985.
  • Anderson BD, Higuchi WI, Raykar PV. Heterogeneity effects on permeability–partition coefficient relationships in human stratum corneum. Pharm Res. 1988;5(9):566–573.
  • Pugh W, Roberts M, Hadgraft J. Epidermal permeability—Penetrant structure relationships: 3. The effect of hydrogen bonding interactions and molecular size on diffusion across the stratum corneum. Int J Pharm. 1996;138(2):149–165.
  • Smith KL. Penetrant characteristics influencing skin absorption. In: Kemppainen BW, Reifenrath WG, editors. Methods for skin absorption. Boca Raton, Florida: CRC Press; 1990. p. 23–34.
  • Roberts MS. Solute-vehicle-skin interactions in percutaneous absorption: the principles and the people. Skin Pharmacol Physiol. 2013;26(4–6):356–370.
  • Ruela ALM, Perissinato AG, MEdS L, et al. Evaluation of skin absorption of drugs from topical and transdermal formulations. Braz J Pharm Sci. 2016;52(3):527–544.
  • Yamaguchi K, Mitsui T, Aso Y, et al. Structure–permeability relationship analysis of the permeation barrier properties of the stratum corneum and viable epidermis/dermis of rat skin. J Pharm Sci. 2008;97(10):4391–4403.
  • Singh P, Roberts M. Local deep tissue penetration of compounds after dermal application: structure-tissue penetration relationships. J Pharmacol Exp Ther. 1996;279(2):908–917.
  • Crutcher W, Maibach HI. The effect of perfusion rate on in vitro percutaneous penetration. J Invest Dermatol. 1969;53(4):264–269.
  • Cross SE, Roberts MS. Subcutaneous absorption kinetics and local tissue distribution of interferon and other solutes. J Pharm Pharmacol. 1993;45(7):606–609.
  • Wu F, Bhansali SG, Law WC, et al. Fluorescence imaging of the lymph node uptake of proteins in mice after subcutaneous injection: molecular weight dependence. Pharm Res. 2012;29(7):1843–1853.
  • Anissimov YG, Roberts MS. Modelling dermal drug distribution after topical application in human. Pharm Res. 2011;28(9):2119–2129.
  • Cross SE, Wu Z, Roberts MS. The effect of protein binding on the deep tissue penetration and efflux of dermally applied salicylic acid, lidocaine and diazepam in the perfused rat hindlimb. J Pharmacol Exp Ther. 1996;277(1):366–374.
  • Jepps OG, Dancik Y, Anissimov YG, et al., Modeling the human skin barrier—Towards a better understanding of dermal absorption. Adv Drug Del Rev. 2013:65(2):152–168.
  • Cross SE, Roberts MS. Targeting local tissues by transdermal application: understanding drug physicochemical properties that best exploit protein binding and blood flow effects. Drug Dev Res. 1999;46(3–4):309–315.
  • Grice JE, Zhang Q, Roberts MS. Chemical structure—skin transport relationships. In: Monteiro-Riviere NA, editor. Toxicology of the skin. Boca Raton, Florida: CRC Press; 2010. p. 69–82.
  • Scheuplein RJ, Blank IH. Permeability of the skin. Physiol Rev. 1971;51(4):702–747.
  • Scheuplein RJ. Mechanism of percutaneous adsorption: I. Routes of penetration and the influence of solubility. J Invest Dermatol. 1965;45(5):334–346.
  • Roberts M, Anderson R, Swarbrick J. Permeability of human epidermis to phenolic compounds. J Pharm Pharmacol. 1977;29(1):677–683.
  • Michaels A, Chandrasekaran S, Shaw J. Drug permeation through human skin: theory and in vitro experimental measurement. Aiche J. 1975;21(5):985–996.
  • Kasting GB, Smith RL, Cooper E. Effect of lipid solubility and molecular size on percutaneous absorption. In: Shroot B, Schaefer H, editors. Skin pharmacokinetics. Vol. 1. Basel: Karger; 1987. p. 138–153.
  • Anderson BD, Raykar PV. Solute structure-permeability relationships in human stratum corneum. J Invest Dermatol. 1989;93(2):280–286.
  • Flynn G. Physicochemical determinants of skin absorption. In: Gerrity TR, Henry CJ, editors. Principles of route-to-route extrapolation for risk assessment. New York: Elsevier; 1990. p. 93–127.
  • Potts RO, Guy RH. Predicting skin permeability. Pharm Res. 1992;9(5):663–669.
  • Barratt M. Quantitative structure-activity relationships for skin permeability. Toxicol In Vitro. 1995;9(1):27–37.
  • Kirchner L. The prediction of skin permeability by using physicochemical data. ATLA. 1997;25:359–370.
  • Potts RO, Guy RH. A predictive algorithm for skin permeability: the effects of molecular size and hydrogen bond activity. Pharm Res. 1995;12(11):1628–1633.
  • Tsakovska I, Pajeva I, Al Sharif M, et al. Quantitative structure-skin permeability relationships. Toxicology. 2017;387:27–42.
  • Pellett M, Roberts M, Hadgraft J. Supersaturated solutions evaluated with an in vitro stratum corneum tape stripping technique. Int J Pharm. 1997;151(1):91–98.
  • Higuchi T. Physical chemical analysis of percutaneous absorption process from creams and ointments. J Soc Cosmet Chem. 1960;11:85–97.
  • Milewski M, Stinchcomb AL. Estimation of maximum transdermal flux of nonionized xenobiotics from basic physicochemical determinants. Mol Pharm. 2012;9(7):2111–2120.
  • Magnusson BM, Anissimov YG, Cross SE, et al., Molecular size as the main determinant of solute maximum flux across the skin. J Invest Dermatol. 2004:122(4):993–999.
  • Blank IH. Penetration of low-molecular-weight alcohols into skin. I. Effect of concentration of alcohol and type of vehicle. J Invest Dermatol. 1964;43:415–420.
  • Samaras EG, Riviere JE, Ghafourian T. The effect of formulations and experimental conditions on in vitro human skin permeation—data from updated EDETOX database. Int J Pharm. 2012;434(1–2):280–291.
  • Majumdar S, Thomas J, Wasdo S, et al. The effect of water solubility of solutes on their flux through human skin in vitro. Int J Pharm. 2007;329(1–2):25–36.
  • Wu Y-T, Anissimov YG, Roberts MS. Introduction to dermatokinetics. In: Narasimha Murthy S, editor. Dermatokinetics of therapeutic agents. Boca Raton Florida: CRC Press; 2011. p. 9–31.
  • Lipinski CA, Lombardo F, Dominy BW, et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Del Rev. 1997;23(1–3):3–25.
  • Choy YB, Prausnitz MR. The rule of five for non-oral routes of drug delivery: ophthalmic, inhalation and transdermal. Pharm Res. 2011;28(5):943–948.
  • Grice JE, Cross SE, Brownlie C, et al., The application of molecular structural predictors of intestinal absorption to screening of compounds for transdermal penetration. J Pharm Pharmacol. 2010:62(6):750–755.
  • Magnusson BM, Pugh WJ, Roberts MS. Simple rules defining the potential of compounds for transdermal delivery or toxicity. Pharm Res. 2004;21(6):1047–1054.
  • Chiang A, Tudela E, Maibach HI. Percutaneous absorption in diseased skin: an overview. J Appl Toxicol. 2012;32(8):537–563.
  • Rutter N. Drug absorption through the skin: a mixed blessing. Arch Dis Child. 1987;62(3):220–221.
  • Gattu S, Maibach H. physiology enhanced absorption through damaged skin: an overview of the in vitro human model. Skin Pharmacol. 2010;23(4):171–176.
  • Halling-Overgaard AS, Kezic S, Jakasa I, et al. Skin absorption through atopic dermatitis skin: a systematic review. Br J Dermatol. 2017;177(1):84–106.
  • Turpeinen M. Influence of age and severity of dermatitis on the percutaneous absorption of hydrocortisone in children. Br J Dermatol. 1988;118(4):517–522.
  • Hata M, Tokura Y, Takigawa M, et al. Assessment of epidermal barrier function by photoacoustic spectrometry in relation to its importance in the pathogenesis of atopic dermatitis. Lab Invest. 2002;82(11):1451–1461.
  • Ortiz PG, Hansen SH, Shah VP, et al. Impact of adult atopic dermatitis on topical drug penetration: assessment by cutaneous microdialysis and tape stripping. Acta Derm Venereol. 2009;89(1):33–38.
  • Jakasa I, De Jongh CM, Verberk MM, et al. Percutaneous penetration of sodium lauryl sulphate is increased in uninvolved skin of patients with atopic dermatitis compared with control subjects. Br J Dermatol. 2006;155(1):104–109.
  • Yoshiike T, Aikawa Y, Sindhvananda J, et al. Skin barrier defect in atopic dermatitis: increased permeability of the stratum corneum using dimethyl sulfoxide and theophylline. J Dermatol Sci. 1993;5(2):92–96.
  • Wester RC, Bucks DA, Maibach HI. In vivo percutaneous absorption of hydrocortisone in psoriatic patients and normal volunteers. J Am Acad Dermatol. 1983;8(5):645–647.
  • Arnott JA, Planey SL. The influence of lipophilicity in drug discovery and design. Expert Opin Drug Discov. 2012;7(10):863–875.
  • Subota V, Mirkov I, Demenesku J, et al. Transdermal toxicity of topically applied anticoagulant rodenticide warfarin in rats. Environ Toxicol Pharmacol. 2016;41:232–240.
  • Ghosh A, Coondoo A. Systemic side effects of topical corticosteroids. In: Lahiri K, editor. A treatise on topical corticosteroids in dermatology. Singapore: Springer; 2018. p. 241–249.
  • Anku WW, Mamo MA, Govender PP. Phenolic compounds in water: sources, reactivity, toxicity and treatment methods. In: Soto-Hernández M, editor. Phenolic compounds-natural sources, importance and applications. London, UK: IntechOpen; 2017. p. 420–443.
  • Daniel AB, Strickland J, Allen D, et al. International regulatory requirements for skin sensitization testing. Regul Toxicol Pharmacol. 2018;95:52–65.
  • Ates G, Steinmetz FP, Doktorova TY, et al. Linking existing in vitro dermal absorption data to physicochemical properties: contribution to the design of a weight-of-evidence approach for the safety evaluation of cosmetic ingredients with low dermal bioavailability. Regul Toxicol Pharmacol. 2016;76:74–78.
  • De Tursi M, Zilli M, Carella C, et al. Skin toxicity evaluation in patients treated with cetuximab for metastatic colorectal cancer: a new tool for more accurate comprehension of quality of life impacts. Onco Targets Ther. 2017;10:3007–3015.
  • Mohammed YH, Moghimi HR, Yousef SA, et al. Efficacy, safety and targets in topical and transdermal active and excipient delivery. In: Dragicevic N, Maibach HIeditors. Percutaneous penetration enhancers drug penetration into/through the skin. Berlin, Heidelberg: Springer; 2017. p. 369–391.
  • Roberts D, Aptula A, Cronin M, et al. Global (Q) SARs for skin sensitisation–assessment against OECD principles. SAR QSAR Environ Res. 2007;18(3–4):343–365.
  • Dearden JC, Hewitt M, Roberts DW, et al., Mechanism-based QSAR modeling of skin sensitization. Chem Res Toxicol. 2015:28(10):1975–1986.
  • Fitzpatrick JM, Roberts DW, Patlewicz G. What determines skin sensitization potency: myths, maybes and realities. The 500 molecular weight cut‐off: an updated analysis. J Appl Toxicol. 2017;37(1):105–116.
  • Greene N, Judson P, Langowski J, et al. Knowledge-based expert systems for toxicity and metabolism prediction: DEREK, StAR and METEOR. SAR QSAR Environ Res. 1999;10(2–3):299–314.
  • Verheyen G, Braeken E, Van Deun K, et al. Evaluation of in silico tools to predict the skin sensitization potential of chemicals. SAR QSAR Environ Res. 2017;28(1):59–73.
  • Chilton ML, Macmillan DS, Steger-Hartmann T, et al. Making reliable negative predictions of human skin sensitisation using an in silico fragmentation approach. Regul Toxicol Pharmacol. 2018;95:227–235.
  • Alves VM, Muratov E, Fourches D, et al. Predicting chemically-induced skin reactions. Part II: QSAR models of skin permeability and the relationships between skin permeability and skin sensitization. Toxicol Appl Pharmacol. 2015;284(2):273–280.
  • Fitzpatrick JM, Roberts DW, Patlewicz G. Is skin penetration a determining factor in skin sensitization potential and potency? Refuting the notion of a LogKow threshold for skin sensitization. J Appl Toxicol. 2017;37(1):117–127.
  • Karande P, Jain A, Ergun K, et al. Design principles of chemical penetration enhancers for transdermal drug delivery. PNAS. 2005;102(13):4688–4693.
  • Paudel KS, Milewski M, Swadley CL, et al. Challenges and opportunities in dermal/transdermal delivery. Ther Deliv. 2010;1(1):109–131.
  • Svensson CK. Biotransformation of drugs in human skin. Drug Metab Dispos. 2009;37(2):247–253.
  • Kazem S, Linssen EC, Gibbs S. Skin metabolism phase I and phase II enzymes in native and reconstructed human skin: a short review. Drug Discov Today. 2019;24(9):1899–1910.
  • Waring MJ. Lipophilicity in drug discovery. Expert Opin Drug Discov. 2010;5(3):235–248.
  • Van De Waterbeemd H, Smith DA, Beaumont K, et al. Property-based design: optimization of drug absorption and pharmacokinetics. J Med Chem. 2001;44(9):1313–1333.
  • Jung EC, Maibach HI. Animal models for percutaneous absorption. J Appl Toxicol. 2015;35(1):1–10.
  • Bouvier D, Prieto P, Blaauboer B, et al., Physiologically-based kinetic modelling (PBK modelling): meeting the 3Rs agenda. The report and recommendations of ECVAM workshop 63. Altern Lab Anim. 2007:35(6):661–671.
  • Hansen S, Henning A, Naegel A, et al. In-silico model of skin penetration based on experimentally determined input parameters. Part I: experimental determination of partition and diffusion coefficients. Eur J Pharm Biopharm. 2008;68(2):352–367.
  • Polak S, Ghobadi C, Mishra H, et al., Prediction of concentration–time profile and its inter-individual variability following the dermal drug absorption. J Pharm Sci. 2012:101(7):2584–2595.
  • Anissimov YG, Roberts MS. Diffusion modeling of percutaneous absorption kinetics: 2. Finite vehicle volume and solvent deposited solids. J Pharm Sci. 2001;90(4):504–520.
  • Tylutki Z, Polak S, Wiśniowska B. Top-down, bottom-up and middle-out strategies for drug cardiac safety assessment via modeling and simulations. Curr Pharmacol Rep. 2016;2(4):171–177.
  • Macpherson SE, Barton CN, Bronaugh RL. Use of in vitro skin penetration data and a physiologically based model to predict in vivo blood levels of benzoic acid. Toxicol Appl Pharmacol. 1996;140(2):436–443.
  • Poet TS, Weitz KK, Gies RA, et al. PBPK modeling of the percutaneous absorption of perchloroethylene from a soil matrix in rats and humans. Toxicol Sci. 2002;67(1):17–31.
  • Norman AM, Kissel JC, Shirai JH, et al. Effect of PBPK model structure on interpretation of in vivo human aqueous dermal exposure trials. Toxicol Sci. 2008;104(1):210–217.
  • Dancik Y, Troutman JA, Jaworska J. A framework incorporating the impact of exposure scenarios and application conditions on risk assessment of chemicals applied to skin. In Silico Pharmacol. 2013;1(1):1–15.
  • Krishnatry AS, Damian-Iordache V, Lloyd R, et al. Novel Skin PBPK model in Action: clindamycin and Tazarotene Modeling. Poster presented at: American Association of Pharmaceutical Scientists (AAPS); 2014; San Diego, CA. [Accessed 2020 May 13]. Available from: https://www.simulations-plus.com/assets/Krishnatry-Poster-AAPS2014-Dermal-Model-Applications.pdf
  • Sawyer ME, Evans MV, Wilson CA, et al. Development of a human physiologically based pharmacokinetic (PBPK) model for dermal permeability for lindane. Toxicol Lett. 2016;245:106–109.
  • Kattou P, Lian G, Glavin S, et al. Development of a two-dimensional model for predicting transdermal permeation with the follicular pathway: demonstration with a caffeine study. Pharm Res. 2017;34(10):2036–2048.
  • Bogen KT, Singhal A. Malathion dermal permeability in relation to dermal load: assessment by physiologically based pharmacokinetic modeling of in vivo human data. J Environ Sci Heal B. 2017;52(2):138–146.
  • Cascella V, Andreassen M, Husøy T, et al. Modeling and simulation of triclosan kinetics and distribution in humans using PBPK model. In: Lars Erik Ø, Komulainen T, Bye RT, et al. editors. Proceedings of the 59th conference on simulation and modelling (SIMS 59); 2018; Norway: Oslo Metropolitan University.
  • Poulin P, Collet SH, Atrux-Tallau N, et al. Application of the tissue composition–based model to minipig for predicting the volume of distribution at steady state and dermis-to-plasma partition coefficients of drugs used in the physiologically based pharmacokinetics model in dermatology. J Pharm Sci. 2019;108(1):603–619.
  • Rajoli RK, Flexner C, Chiong J, et al. Modelling the intradermal delivery of microneedle array patches for long-acting antiretrovirals using PBPK. Eur J Pharm Biopharm. 2019;144:101–109.
  • Clewell III HJ, Andersen ME, Wills RJ, et al. A physiologically based pharmacokinetic model for retinoic acid and its metabolites. J Am Acad Dermatol. 1997;36(3):S77–S85.
  • US FDA. Physiologically based pharmacokinetic analyses—format and content guidance for industry. 2016. [Accessed 2020 May 13]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/physiologically-based-pharmacokinetic-analyses-format-and-content-guidance-industry
  • Patel N, Benkali K, Osman-Ponchet H, et al. Development and verification of PBPK model for a topical cream formulation of trifarotene to simulate local and systemic exposure and model application to simulate potential cyp-mediated drug-drug interactions. Poster presented at: American Association of Pharmaceutical Scientists (AAPS), 2017; San Diego, CA. [Accessed 2020 May 13]. Available from: https://www.certara.com/wp-content/uploads/Resources/Posters/Patel-AAPS-2017-Galderma-Trifarotine.pdf
  • Dearden J, Cronin M, Kaiser K. How not to develop a quantitative structure–activity or structure–property relationship (QSAR/QSPR). SAR QSAR Environ Res. 2009;20(3–4):241–266.
  • Bouwman T, Cronin M, Bessems J, et al. Improving the applicability of (Q) SARs for percutaneous penetration in regulatory risk assessment. Hum Exp Toxicol. 2008;27(4):269–276.
  • Bois FY, Ochoa JGD, Gajewska M, et al. Multiscale modelling approaches for assessing cosmetic ingredients safety. Toxicology. 2017;392:130–139.
  • Dancik Y, Jepps OG, Roberts MS. Physiologically based pharmacokinetics and pharmacodynamics of skin. In: Roberts MS, Walters KA, editors. Dermal absorption and toxicity assessment. New York: Informa Healthcare; 2007. p. 179–207.
  • Lien EJ, Tong GL. Physicochemical properties and percutaneous absorption of drugs. J Soc Cosmet Chem. 1973;24:371–384.
  • Williams AC, Barry BW. Penetration enhancers. Adv Drug Del Rev. 2012;64:128–137.
  • Kaushik D, Batheja P, Kilfoyle B, et al. Percutaneous permeation modifiers: enhancement versus retardation. Expert Opin Drug Deliv. 2008;5(5):517–529.
  • Estrada E, Uriarte E, Gutierrez Y, et al. Quantitative structure-toxicity relationships using TOPS-MODE. 3. Structural factors influencing the permeability of commercial solvents through living human skin. SAR QSAR Environ Res. 2003;14(2):145–163.
  • Pugh W, Wong R, Falson F, et al. Discriminant analysis as a tool to identify compounds with potential as transdermal enhancers. J Pharm Pharmacol. 2005;57(11):1389–1396.
  • Ding B, Fu X, Liang W. Branched-chain alkanols as skin permeation enhancers: quantitative structure-activity relationships. Pharmazie. 2006;61(4):298–300.
  • Moss G, Shah A, Adams R, et al. The application of discriminant analysis and machine learning methods as tools to identify and classify compounds with potential as transdermal enhancers. Eur J Pharm Sci. 2012;45(1–2):116–127.
  • Azarbayjani AF, Khu JV, Chan YW, et al. Development and characterization of skin permeation retardants and enhancers: A comparative study of levothyroxine‐loaded PNIPAM, PLA, PLGA and EC microparticles. Biopharm Drug Dispos. 2011;32(7):380–388.
  • Leite-Silva VR, De Almeida MM, Fradin A, et al. Delivery of drugs applied topically to the skin. Expert Rev Dermatol. 2012;7(4):383–397.
  • Roy K, Das RN, Ambure P, et al. Be aware of error measures. Further studies on validation of predictive QSAR models. Chemometr Intell Lab Syst. 2016;152:18–33.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.