Ethanol and Other Alcohols: Old Enhancers, Alternative Perspectives

Abstract

Alcohols, such as ethanol and propylene glycol, are among the most intensively studied penetration enhancers in the field of topical drug delivery. Much has been written concerning the use of these versatile solvents with generally positive results being produced and alcohols featuring in a number of commercially available products. Much has also been published regarding the mechanisms underpinning penetration enhancement. In the first instance, ethanol is typically used as a co-solvent in order to increase the donor concentrations of poorly soluble drugs in aqueous solutions. This would thus provide increased fluxes by creating a higher chemical potential within the vehicle. At the tissue level, numerous papers have focussed on processes occurring within the stratum corneum as a consequence of the applied alcoholic formulation. A common theme relates to the modulation of skin lipid domains, which become more leaky thus facilitating increased drug partitioning and permeation. Such processes are sometimes claimed to be reversible within a short timescale, which does not fit well with other observations of the leaching of skin lipids, particularly when high levels of alcohols are dosed to the skin. In addition to reviewing the aforementioned, this Chapter seeks to offer some alternative perspectives relating to the mechanisms by which penetration enhancement is achieved by alcohols and probably other chemical permeation enhancers too. It is proposed that interactions and modulations within the stratum corneum are only part of the process and that a fuller picture only emerges when the permeation of the drug is viewed alongside the permeation of enhancer/vehicle. Firstly, dissolution is a thermodynamic process – energy is released as a solute undergoes solvation – and to reverse the process requires input of equal or more energy. Secondly, it is known that alcohols penetrate the skin. Thirdly, studies on the relationship between levels of alcohol and solute penetrating the skin indicate that co-permeation/drag effects are of key importance.

Keywords

Skin penetration Chemical enhancer Alcohol Ethanol Propylene glycol Co-permeation Solvation 

References

  1. Ahmed-Lecheheb D, Cunat L, Hartemann P, Hautemanière A (2012) Dermal and pulmonary absorption of ethanol from alcohol-based hand rub. J Hosp Infect 81:31–35Google Scholar
  2. Andanson JM, Hadgraft J, Kazarian SG (2009) In situ permeation study of drug through the stratum corneum using attenuated total reflection Fourier transform infrared spectroscopic imaging. J Biomed Opt 14:034011CrossRefPubMedGoogle Scholar
  3. Andega S, Kanikkannan N, Singh M (2001) Comparison of the effect of fatty alcohols on the permeation of melatonin between porcine and human skin. J Control Release 77:17–25CrossRefPubMedGoogle Scholar
  4. Bendas B, Schmalfuβ U, Neubert R (1995) Influence of propylene glycol as cosolvent on mechanisms of drug transport from hydrogels. Int J Pharm 116:19–30CrossRefGoogle Scholar
  5. Benson H (2005) Transdermal drug delivery: penetration enhancement techniques. Curr Drug Deliv 2:23–33CrossRefPubMedGoogle Scholar
  6. Berner B, Mazzenga GC, Otte JH, Steffens RJ, Juang RH, Ebert CD (1989) Ethanol: water mutually enhanced transdermal therapeutic system II: skin permeation of ethanol and nitroglycerin. J Pharm Sci 78:402–407CrossRefPubMedGoogle Scholar
  7. Bommanan D, Potts R, Guy RH (1991) Examination of the effect of ethanol on human stratum corneum in vivo using infrared spectroscopy. J Control Release 16:299–304CrossRefGoogle Scholar
  8. Bowen JL, Heard CM (2006) Film drying and complexation effects in the simultaneous skin permeation of ketoprofen and propylene glycol from simple gel formulations. Int J Pharm 307:251–257CrossRefPubMedGoogle Scholar
  9. Brand RM, Jendrzejewski JL, Charron AR (2007) Potential mechanisms by which a single drink of alcohol can increase transdermal absorption of topically applied chemicals. Toxicology 235:141–149CrossRefPubMedGoogle Scholar
  10. Chantasart D, Li SK, He N, Warner KS, Prakongpan S, Higuchi WI (2004) Mechanistic studies of branched-chain alkanols as skin permeation enhancers. J Pharm Sci 93:762–779CrossRefPubMedGoogle Scholar
  11. Dias M, Naik A, Guy RH et al (2008) In vivo infrared spectroscopy studies of alkanol effects on human skin. Eur J Pharm Biopharm 69:1171–1175CrossRefPubMedGoogle Scholar
  12. Du Plessis J, Pugh WJ, Judefeind A, Hadgraft J (2001) The effect of hydrogen bonding on diffusion across model membranes: consideration of the number of H-bonding groups. Eur J Pharm Sci 13:135–141CrossRefPubMedGoogle Scholar
  13. Duracher L, Blasco L, Hubaud J-C et al (2009) The influence of alcohol, propylene glycol and 1,2-pentanediol on the permeability of hydrophilic model drug through excised pig skin. Int J Pharm 374:39–45CrossRefPubMedGoogle Scholar
  14. Fang C, Liu Y, Ye X et al (2008) Synergistically enhanced transdermal permeation and topical analgesia of tetracaine gel containing menthol and ethanol in experimental and clinical studies. Eur J Pharm Biopharm 68:735–740CrossRefPubMedGoogle Scholar
  15. Farajtabar A, Jaberi F, Gharib F (2011) Preferential solvation and solvation shell composition of free base and protonated 5, 10, 15, 20-tetrakis(4-sulfonatophenyl)porphyrin in aqueous organic mixed solvents. Spectrochim Acta A 83:213–220CrossRefGoogle Scholar
  16. Fasano WJ, ten Berge WF, Banton MI et al (2011) Dermal penetration of propylene glycols: measured absorption across human abdominal skin in vitro and comparison with a QSAR model. Toxicol In Vitro 25:1664–1670CrossRefPubMedGoogle Scholar
  17. Fiume MM, Bergfeld WF, Belsito DV et al (2012) Safety assessment of propylene glycol, tripropylene glycol, and propylene glycols as used in cosmetics. Int J Toxicol 31:245S–260SCrossRefPubMedGoogle Scholar
  18. Flynn GL, Durrheim H, Higuchi WI (1981) Permeation of hairless mouse skin II: membrane sectioning techniques and influence on alkanol permeabilities. J Pharm Sci 70:52–56CrossRefPubMedGoogle Scholar
  19. Friend D, Catz P, Heller J, Reid J, Baker R (1988) Transdermal delivery of levonorgestrel I. Alkanols as permeation enhancers. J Control Release 7:243–250CrossRefGoogle Scholar
  20. Funke AP, Schiller R, Motzkus HW, Gunther C, Muller RH, Lipp R (2002) Transdermal delivery of highly lipophilic drugs: in vitro fluxes of antiestrogens, permeation enhancers, and solvents from liquid formulations. Pharm Res 19:661–668CrossRefPubMedGoogle Scholar
  21. Geusens B, Van Gele M, Braat S (2010) Flexible nanosomes (secosomes) enable efficient siRNA delivery in cultured primary skin cells and in the viable epidermis of ex vivo human skin. Adv Funct Mater 20:4077–4090CrossRefGoogle Scholar
  22. Guo X, Guo ZY, Wei HJ et al (2010) In vivo quantification of propylene glycol, glucose and glycerol diffusion in human skin with optical coherence tomography. Laser Phys 20:1849–1855CrossRefGoogle Scholar
  23. Heard CM, Screen C (2008) Probing the permeation enhancement of mefenamic acid by ethanol across full thickness skin, heat-separated epidermal membrane and heat-separated dermal membrane. Int J Pharm 349:323–325CrossRefPubMedGoogle Scholar
  24. Heard CM, Gallagher SJ, Harwood JL, Maguire PB (2003) The in vitro delivery of NSAIDs across skin was in proportion to the delivery of essential fatty acids in the vehicle – evidence that solutes permeate skin associated with their solvation cages? Int J Pharm 261:165–169CrossRefPubMedGoogle Scholar
  25. Heard CM, Congiatu C, Gallagher SJ, Harwood JL, Karia C, McGuigan C, Nemcova M, Nouskova T, Thomas CP (2005) Preferential π-π complexation between tamoxifen and borage oil/γ linolenic acid: transcutaneous delivery and NMR spectral modulation. Int J Pharm 302:47–55CrossRefPubMedGoogle Scholar
  26. Heard CM, Kung D, Thomas CP (2006) Skin penetration enhancement of mefenamic acid by ethanol and 1,8-cineole can be explained by the pull effect. Int J Pharm 321:167–170CrossRefPubMedGoogle Scholar
  27. Higuchi WI (1962) Analysis of data on the medicament release from ointments. J Pharm Sci 51:802–804CrossRefPubMedGoogle Scholar
  28. Ho S, Calder RJ, Heard CM, Thomas CP (2004) In vitro transcutaneous delivery of tamoxifen and γ linolenic acid from a borage oil formulation containing ethanol and 1,8-cineole. J Pharm Pharmacol 56:1–8Google Scholar
  29. Hoelgaard A, Møllgaard B (1985) Dermal drug delivery. Improvement by choice of vehicle or drug derivative. J Control Release 2:111–120CrossRefGoogle Scholar
  30. Horita A, Weber LJ (1964) Skin penetrating property of drugs dissolved in dimethylsulfoxide (DMSO) and other vehicles. Life Sci 3:1389–1395CrossRefPubMedGoogle Scholar
  31. Hostýnek JJ, Dreher F, Nakada T, Schwindt D, Anigbogu A, Maibach HI (2001) Human stratum corneum adsorption of nickel salts. Investigation of depth profiles by tape stripping in vivo. Acta Derm Venereol Suppl 212:11–18Google Scholar
  32. Houston DM, Rogers S, Heard CM. Skin penetration enhancement of caffeine by ethanol and propylene glycol: probing the co-permeation effect. Unpublished dateGoogle Scholar
  33. Ibrahim SA, Li SK (2009) Effects of solvent deposited enhancers on transdermal permeation and their relationship with Emax. J Control Release 136:117–124PubMedCentralCrossRefPubMedGoogle Scholar
  34. Ikeda Y, Higashi K, Moribe K, Yamamoto K (2012) Enhanced skin permeation of piroxicam and pranoprofen induced from nanoparticles dispersed in propylene glycol aqueous solution. J Drug Deliver Sci Technol 22:131–137CrossRefGoogle Scholar
  35. Jaimes-Lizcano YA, Lawson LB, Papadopoulos KD (2011) Oil-Frozen W-1/O/W-2 double emulsions for dermal biomacromolecular delivery containing ethanol as chemical penetration enhancer. J Pharm Sci 100:1398–1406CrossRefPubMedGoogle Scholar
  36. Kadir R, Stempler D, Liron Z, Cohen S (1987) Delivery of theophylline into excised human-skin from alkanoic acid-solutions - a push-pull mechanism. J Pharm Sci 76:774–779CrossRefPubMedGoogle Scholar
  37. Kim K, Oh S (2011) Calcitonin transport through skin using iontophoresis. J Pharm Invest 41:9–17CrossRefGoogle Scholar
  38. Kramer A, Below H, Bieber N et al (2007) Quantity of ethanol absorption after excessive hand disinfection using three commercially available hand rubs is minimal and below toxic levels for humans. BMC Infect Dis 7:117PubMedCentralCrossRefPubMedGoogle Scholar
  39. Kumar R, Keyes T (2012) The relation between the structure of the first solvation shell and the IR spectra of aqueous solutions. J Biol Phys 38:75–83PubMedCentralCrossRefPubMedGoogle Scholar
  40. Kurihara-Bergstrom T, Knutson K, DeNoble LJ, Goates CY (1990) Percutaneous absorption enhancement of an ionic molecule by ethanol-water systems in human skin. Pharm Res 7:762–766CrossRefPubMedGoogle Scholar
  41. Leichtnam ML, Rolland H, Wüthrich P, Guy RH (2006) Formulation and evaluation of a testosterone transdermal spray. J Pharm Sci 95:1693–1702Google Scholar
  42. Levang AK, Zhao K, Singh J (1999) Effect of ethanol/propylene glycol on the in vitro percutaneous absorption of aspirin, biophysical changes and macroscopic barrier properties of the skin. Int J Pharm 30:255–263CrossRefGoogle Scholar
  43. Liu P, Kurighara-Bergstrom T, Good WR (1991) Cotransport of estradiol and ethanol through human skin in vitro: understanding the permeant/enhancer flux relationship. Pharm Res 8:938–944CrossRefPubMedGoogle Scholar
  44. Liu P, Cettina M, Wong J (2009) Effects of isopropanol-isopropyl myristate binary enhancers on in vitro transport of estradiol in human epidermis: a mechanistic evaluation. J Pharm Sci 98:565–572CrossRefPubMedGoogle Scholar
  45. Megrab NA, Williams AC, Barry BW (1995) Oestradiol permeation across human skin, silastic and snake skin membranes: the effects of ethanol/water co-solvent systems. Int J Pharm 116:101–112CrossRefGoogle Scholar
  46. Morimoto H, Wada Y, Seki T, Sugibayashi K (2002) In vitro skin permeation of morphine hydrochloride during the finite application of penetration-enhancing system containing water, ethanol and L-menthol. Biol Pharm Bull 25:134–136CrossRefPubMedGoogle Scholar
  47. Moser K, Kriwet K, Froehlich C, Kalia YN, Guy RH (2001) Supersaturation: enhancement of skin penetration and permeation of a lipophilic drug. Pharm Res 18:1006–1011CrossRefPubMedGoogle Scholar
  48. Ng WC, Ng MH, Lee KS et al (2009) Investigation on ethanol and propylene glycol as enhancers for skin-electrode conductivity in bioelectrical potential measurement. Funct Mater Lett 2:175–177CrossRefGoogle Scholar
  49. Oliveira G, Hadgraft J, Lane ME (2012) The role of vehicle interactions on permeation of an active through model membranes and human skin. Int J Cosmetic Sci 34:536–545CrossRefGoogle Scholar
  50. Pardo A, Shiri Y, Cohen S (1991) Partial molal volumes and solubilities of physostigmine in isopropanol-isopropyl myristate solvents in relation to skin penetrability. J Pharm Sci 80:567–572CrossRefPubMedGoogle Scholar
  51. Patel MR, Patel RB, Parikh JR, Solanki AB, Patel BG (2009) Effect of formulation components on the in vitro permeation of microemulsion drug delivery system of fluconazole. AAPS PharmSciTech 10:917–923Google Scholar
  52. Pendlington RU, Whittle E, Robinson JA, Howes D (2001) Fate of ethanol topically applied to skin. Food Chem Toxicol 39:169–174CrossRefPubMedGoogle Scholar
  53. Perlovich GL, Bauer-Brandl A (2004) Solvation of drugs as a key for understanding partition and passive transport as exemplified by NSAIDs. Curr Drug Deliv 1:213–226CrossRefPubMedGoogle Scholar
  54. Perlovich P, Kurkov AN, Kinchin A, Bauer-Brandl A (2003) Thermodynamics of solutions IV: solvation of ketoprofen in comparison with other NSAIDS. J Pharm Sci 92:2502–2511CrossRefPubMedGoogle Scholar
  55. Perlovich GL, Kurkov SV, Kinchin AN, Bauer-Brand A (2004) Solvation and hydration characteristics of ibuprofen and acetyl salicylic acid. AAPS PharmSci 6:3CrossRefGoogle Scholar
  56. Pershing LK, Lambert LD, Knutson K (1990) Mechanism of ethanol-enhanced estradiol permeation across human skin in vivo. Pharm Res 7:170–175CrossRefPubMedGoogle Scholar
  57. Potts RO, Guy RH (1991) Predicting skin permeability. Pharm Res 9:663–669CrossRefGoogle Scholar
  58. Priborsky J, Takayama K, Nagai T et al (1987) Combination effect of penetration enhancers and propylene glycol on in vitro transdermal absorption of insulin. Drug Des Deliv 2:91–97PubMedGoogle Scholar
  59. Pugh WJ (1999) Relationship between H-bonding of penetrants to stratum corneum lipids and diffusion. In: Bronaugh RL, Maibach HI (eds) Percutaneous Absorption: drugs, Cosmetics, Mechanisms, Methods, 3rd edn. Marcel Dekker, New York, Chapter 9Google Scholar
  60. Reid ML, Jones SA, Brown M (2009) Transient drug supersaturation kinetics of beclomethasone dipropionate in rapidly drying films. Int J Pharm 371:114–119CrossRefPubMedGoogle Scholar
  61. Santos P, Watkinson AC, Hadgraft J, Lane ME (2012) Influence of penetration enhancer on drug permeation from volatile formulations. Int J Pharm 439:260–268CrossRefPubMedGoogle Scholar
  62. Santoyo S, Ygartua P (2000) Effect of skin pre-treatment with fatty acids on percutaneous absorption and skin retention of piroxicam after its topical application. Eur J Pharm Biopharm 50:245–250CrossRefPubMedGoogle Scholar
  63. Schaefer-Korting M, Mahmoud A, Borgia SL et al (2008) Reconstructed epidermis and full-thickness skin for absorption testing: influence of the vehicles used on steroid permeation. Altern Lab Anim 36:441–452Google Scholar
  64. Squillante E, Needham T, Maniar A, Kislaliogu S, Zia H (1998) Co-diffusion of propylene glycol and dimethyl isosorbide in hairless mouse skin. Eur J Pharm Biopharm 46:265–271CrossRefPubMedGoogle Scholar
  65. Tanojo H, Bouwstra JA, Junginger HE, Bodde HE (1999) Thermal analysis studies on human skin and skin barrier modulation by fatty acids and propylene glycol. J Therm Anal Calorim 57:313–322CrossRefGoogle Scholar
  66. Tfayli A, Emmanuelle G, Michel M, Baillet-Guffroy A (2012) Molecular interactions of penetration enhancers within ceramides organization: a Raman spectroscopy approach. Analyst 137:5002–5010CrossRefPubMedGoogle Scholar
  67. Thomas CP, Davison Z, Heard CM (2007) Probing the skin permeation of fish oil/EPA and ketoprofen 3. Influence of fish oil/ketoprofen on epidermal COX-2 and LOX. Prostaglandins Leukot Essent Fatty Acids 76:357–362CrossRefPubMedGoogle Scholar
  68. Twist JN, Zatz JL (1986) Influence of solvents on paraben permeation through idealized skin model membranes. J Soc Cosmet Chem 37:429–444Google Scholar
  69. Vaddi HK, Ho PC, Chan YW, Chan SY (2002) Terpenes in ethanol: haloperidol permeation and partition through human skin and stratum corneum changes. J Control Release 81:121–133CrossRefPubMedGoogle Scholar
  70. Van der Merwe D, Riviere JE (2005) Comparative studies on the effects of water, ethanol and water/ethanol mixtures on chemical partitioning into porcine stratum corneum and silastic membrane. Toxicol In Vitro 19:69–77CrossRefPubMedGoogle Scholar
  71. Van Hulst M, van Gompel AHP, Cornwell PA (1998) Percutaneous absorption and skin metabolism: the effects of formulation excipients on metabolism. In: Brain KR, James VJ, Walters KA (eds) Perspectives in percutaneous penetration, vol 5b. STS Publishing, Cardiff, pp 45–49Google Scholar
  72. Verma DD, Fahr A (2004) Synergistic penetration enhancement effect of ethanol and phospholipids on the topical delivery of cyclosporin A. J Control Release 97:55–66CrossRefPubMedGoogle Scholar
  73. Wang LH, Wang CC, Kuo SC (2008) Vehicle and enhancer effects on human skin penetration of aminophylline from cream formulations: Evaluation in vivo. Int J Cosmet Sci 30:310Google Scholar
  74. Williams AC, Barry BW (2004) Penetration enhancers. Adv Drug Deliv Rev 56:603–618CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Cardiff School of Pharmacy and Pharmaceutical SciencesCardiff UniversityCardiffUK

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