AAPS PharmSciTech

, Volume 11, Issue 3, pp 1068–1083 | Cite as

Percutaneous Penetration Modifiers and Formulation Effects: Thermal and Spectral Analyses

Research Article

Abstract

The study investigated the formulation effects of laurocapram and iminosulfurane derived penetration modifiers on human stratum corneum using thermal and spectral analyses. Firstly, formulations of penetration modifiers were assessed as enhancers/retardants using the model permeant, diethyl-m-toluamide followed by investigation of their mechanisms of action using differential scanning calorimetry (DSC) and attenuated total reflectance Fourier-transform infra-red spectroscopy. The penetration modifiers investigated were laurocapram, 3-dodecanoyloxazolidin-2-one (N-0915), S,S-dimethyl-N-(4-bromobenzoyl) iminosulfurane (DMBIS), S,S-dimethyl-N-(2-methoxycarbonylbenzenesulfonyl) iminosulfurane (DMMCBI) and tert-butyl 1-dodecyl-2-oxoazepan-3-yl-carbamate (TBDOC) that were formulated in either water, propylene glycol (PG), ethanol or polyethylene glycol 400 (PEG 400). The results explain the mechanism for the first time why an enhancer can become a retardant or vice versa depending upon the vehicle in which it is applied to the skin. DSC indicated that penetration modifier formulations enhanced permeation of active mainly by disruption and fluidization of the stratum corneum lipid bilayers while IR data indicated characteristic blue shifts with decreases in peak intensity. On the other hand, DSC of penetration modifier formulations showing retardation depicted elevated T m2 with a strengthening of lipid–protein complex while IR results indicated formation of multiple peaks around 1,738 cm−1 transition in stratum corneum spectra suggesting retardation may be caused by organization of SC lipids by increased H-bonding.

Key words

differential scanning calorimetry enhancers infra-red spectroscopy penetration modifiers retardants stratum corneum 

Abbreviations

ATR-FTIR

Attenuated total reflectance Fourier-transform infra-red spectroscopy

DEET

Diethyl-m-toluamide

DMBIS

S,S-Dimethyl-N-(4-bromobenzoyl) iminosulfurane

DMMCBI

S,S-dimethyl-N-(2-methoxycarbonylbenzenesulfonyl) iminosulfurane

DSC

Differential scanning calorimetry

H

Mean enthalpy

H-bond

Hydrogen bond

HSD

Honestly significantly different

N-0915

3-Dodecanoyloxazolidin-2-one

PEG 400

Polyethylene glycol 400

PG

Propylene glycol

SC

Stratum corneum

TBDOC

tert-Butyl 1-dodecyl-2-oxoazepan-3-yl-carbamate

Tm

Mean transition temperature

Notes

Acknowledgments

The authors express gratitude to Dr James Chapman (University of South Carolina, Columbia) for providing N-0915 and TBDOC. In addition, we acknowledge the assistance of Drs. A. Joy, D. Bolikal, S. Murthy, J. Khan and J. Kohn from the NJ Center for Biomaterials for providing compounds laurocapram, DMMCBI, and DMBIS and DSC facility. Partial funding provided by the NJ Center for Biomaterials, Rutgers—The State University of New Jersey.

References

  1. 1.
    Wertz PW. Epidermal lipids. Semin Dermatol. 1992;11(2):106–13.PubMedGoogle Scholar
  2. 2.
    Kaushik D, Batheja P, Kilfoyle B, Rai V, Michniak-Kohn B. Percutaneous permeation modifiers: enhancement versus retardation. Expert Opin Drug Deliv. 2008;5(5):517–29.CrossRefPubMedGoogle Scholar
  3. 3.
    Kaushik D, Costache A, Michniak-Kohn B. Percutaneous penetration modifiers and formulation effects. Int J Pharm. 2010;386(1–2):42–51.CrossRefPubMedGoogle Scholar
  4. 4.
    Hoogstraate AJ, Verhoef J, Brussee J, IJzerman AP, Spies F, Boddé HE. Kinetics, ultrastructural aspects and molecular modelling of transdermal peptide flux enhancement by N-alkylazacycloheptanones. Int J Pharm. 1991;76(1–2):37–47.CrossRefGoogle Scholar
  5. 5.
    Sintov AC, Zhang PJ, Michniak-Kohn BB. Cutaneous biotransformation of N-(4-bromobenzoyl)-S,S-dimethyliminosulfurane and its product, 4-bromobenzamide, leading to percutaneous penetration enhancement of drugs: initial evidence using hydrocortisone. J Control Release. 2009;133(1):44–51.CrossRefPubMedGoogle Scholar
  6. 6.
    Hadgraft J, Peck J, Williams DG, Pugh WJ, Allan G. Mechanisms of action of skin penetration enhancers/retarders: Azone and analogues. Int J Pharm. 1996;141(1–2):17–25.CrossRefGoogle Scholar
  7. 7.
    Kim N, El-Khalili M, Henary MM, Strekowski L, Michniak BB. Percutaneous penetration enhancement activity of aromatic S,S-dimethyliminosulfuranes. Int J Pharm. 1999;187(2):219–29.CrossRefPubMedGoogle Scholar
  8. 8.
    Purdon C. Synthesis and evaluation of aminocaprolactam derivatives as novel skin penetration retarders. [Ph.D. Thesis]. College of Pharmacy, University of South Carolina, Columbia; 2005.Google Scholar
  9. 9.
    Williams A, Barry, BW. Chemical Permeation enhancement. In: Touitou E, Barry, BW, editor. Enhancement in drug delivery. CRC, Taylor & Francis Group; 2006. p. 233–254.Google Scholar
  10. 10.
    Kasting GB, Bhatt VD, Speaker TJ. Microencapsulation decreases the skin absorption of N,N-diethyl-m-toluamide (DEET). Toxicol In Vitro. 2008;22(2):548–52.CrossRefPubMedGoogle Scholar
  11. 11.
    Iscan Y, Hekimoglu S, Sargon MF, Hincal AA. DEET-loaded solid lipid particles for skin delivery: in vitro release and skin permeation characteristics in different vehicles. J Microencapsul. 2006;23(3):315–27.CrossRefPubMedGoogle Scholar
  12. 12.
    Golden GM, Guzek DB, Kennedy AH, McKie JE, Potts RO. Stratum corneum lipid phase transitions and water barrier properties. Biochemistry. 1987;26(8):2382–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Sapra B, Jain S, Tiwary AK. Percutaneous permeation enhancement by terpenes: mechanistic view. AAPS J. 2008;10(1):120–32.CrossRefPubMedGoogle Scholar
  14. 14.
    Windheuser JJ, Haslam JL, Caldwell L, Shaffer RD. The use of N,N-diethyl-m-toluamide to enhance dermal and transdermal delivery of drugs. J Pharm Sci. 1982;71(11):1211–3.CrossRefPubMedGoogle Scholar
  15. 15.
    Van Duzee BF. Thermal analysis of human stratum corneum. J Invest Dermatol. 1975;65(4):404–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Golden GM, Guzek DB, Harris RR, McKie JE, Potts RO. Lipid thermotropic transitions in human stratum corneum. J Invest Dermatol. 1986;86(3):255–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Potts R, Golden GM, Francoeur ML, Mak VHW, Guy RH. Mechanism and enhancement of solute transport across the stratum corneum. J Control Release. 1991;15:249–60.CrossRefGoogle Scholar
  18. 18.
    Leopold CS, Lippold BC. An attempt to clarify the mechanism of the penetration enhancing effects of lipophilic vehicles with differential scanning calorimetry (DSC). J Pharm Pharmacol. 1995;47(4):276–81.PubMedGoogle Scholar
  19. 19.
    Tanojo H, Bouwstra JA, Junginger HE, Bodde' HE. Thermal analysis studies on human skin and skin barrier modulation by fatty acids and propylene glycol. J Therm Anal Calorim. 1999;57(1):313–22.CrossRefGoogle Scholar
  20. 20.
    Yamane MA, Williams AC, Barry BW. Effects of terpenes and oleic acid as skin penetration enhancers towards 5-fluorouracil as assessed with time; permeation, partitioning and differential scanning calorimetry. Int J Pharm. 1995;116(2):237–51.CrossRefGoogle Scholar
  21. 21.
    Cornwell PA, Barry BW, Stoddart CP, Bouwstra JA. Wide-angle X-ray diffraction of human stratum corneum: effects of hydration and terpene enhancer treatment. J Pharm Pharmacol. 1994;46(12):938–50.PubMedGoogle Scholar
  22. 22.
    Van Hal DA, Jeremiasse E, Junginger HE, Spies F, Bouwstra JA. Structure of fully hydrated human stratum corneum: a freeze-fracture electron microscopy study. J Invest Dermatol. 1996;106(1):89–95.CrossRefPubMedGoogle Scholar
  23. 23.
    Menon GK, Elias PM. Morphologic basis for a pore-pathway in mammalian stratum corneum. Skin Pharmacol. 1997;10(5–6):235–46.CrossRefPubMedGoogle Scholar
  24. 24.
    Ogiso T, Iwaki M, Bechako K, Tsutsumi Y. Enhancement of percutaneous absorption by laurocapram. J Pharm Sci. 1992;81(8):762–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2004;56(5):603–18.CrossRefPubMedGoogle Scholar
  26. 26.
    Francoeur ML, Golden GM, Potts RO. Oleic acid: its effects on stratum corneum in relation to (trans)dermal drug delivery. Pharm Res. 1990;7(6):621–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Melot M, Pudney PD, Williamson AM, Caspers PJ, Van Der Pol A, Puppels GJ. Studying the effectiveness of penetration enhancers to deliver retinol through the stratum cornum by in vivo confocal Raman spectroscopy. J Control Release. 2009;138(1):32–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Lawson E, Edwards HGM, Williams AC, Barry BW. Applications of Raman spectroscopy to skin research. Skin Res Technol. 1997;3(3):147–53.CrossRefGoogle Scholar
  29. 29.
    Cornwell PA, Barry BW, Bouwstra JA, Gooris GS. Modes of action of terpene penetration enhancers in human skin; Differential scanning calorimetry, small-angle X-ray diffraction and enhancer uptake studies. Int J Pharm. 1996;127(1):9–26.CrossRefGoogle Scholar
  30. 30.
    Mantsch HH, Chapman D. Infrared spectroscopy of biomolecules. New York: Wiley-Liss; 1996.Google Scholar
  31. 31.
    Garidel P. Mid-FTIR- Microspectroscopy of stratum corneum single cells and stratum corneum tissue. Phys Chem Chem Phys. 2002;4:5671–7.CrossRefGoogle Scholar
  32. 32.
    Panchagnula R, Salve PS, Thomas NS, Jain AK, Ramarao P. Transdermal delivery of naloxone: effect of water, propylene glycol, ethanol and their binary combinations on permeation through rat skin. Int J Pharm. 2001;219(1–2):95–105.CrossRefPubMedGoogle Scholar
  33. 33.
    Tamm LK, Tatulian SA. Infrared spectroscopy of proteins and peptides in lipid bilayers. Q Rev Biophys. 1997;30(4):365–429.CrossRefPubMedGoogle Scholar
  34. 34.
    Garidel P, Blume A, Hubner W. A Fourier transform infrared spectroscopic study of the interaction of alkaline earth cations with the negatively charged phospholipid 1, 2-dimyristoyl-sn-glycero-3-phosphoglycerol. Biochim Biophys Acta. 2000;1466(1–2):245–59.PubMedGoogle Scholar
  35. 35.
    Mendelsohn R, Chen HC, Rerek ME, Moore DJ. Infrared microspectroscopic imaging maps the spatial distribution of exogenous molecules in skin. J Biomed Opt. 2003;8(2):185–90.CrossRefPubMedGoogle Scholar
  36. 36.
    Zhang G, Moore DJ, Flach CR, Mendelsohn R. Vibrational microscopy and imaging of skin: from single cells to intact tissue. Anal Bioanal Chem. 2007;387(5):1591–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Zhang G, Moore DJ, Mendelsohn R, Flach CR. Vibrational microspectroscopy and imaging of molecular composition and structure during human corneocyte maturation. J Invest Dermatol. 2006;126(5):1088–94.CrossRefPubMedGoogle Scholar
  38. 38.
    Brandenburg K, Seydel U. Infrared spectroscopy of glycolipids. Chem Phys Lipids. 1998;96(1–2):23–40.CrossRefPubMedGoogle Scholar
  39. 39.
    Nair VB, Panchagnula R. Effect of iontophoresis and fatty acids on permeation of arginine vasopressin through rat skin. Pharmacol Res. 2003;47(6):563–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Takahashi K, Sakano H, Numata N, Kuroda S, Mizuno N. Effect of fatty acid diesters on permeation of anti-inflammatory drugs through rat skin. Drug Dev Ind Pharm. 2002;28(10):1285–94. doi: 10.1081/DDC-120015362.CrossRefPubMedGoogle Scholar
  41. 41.
    Dias M, Naik A, Guy RH, Hadgraft J, Lane ME. In vivo infrared spectroscopy studies of alkanol effects on human skin. Eur J Pharm Biopharm. 2008;69(3):1171–5.CrossRefPubMedGoogle Scholar
  42. 42.
    Kim YC, Park JH, Ludovice PJ, Prausnitz MR. Synergistic enhancement of skin permeability by N-lauroylsarcosine and ethanol. Int J Pharm. 2008;352(1–2):129–38.PubMedGoogle Scholar
  43. 43.
    Mendelsohn R, Rerek ME, Moore DJ. Infrared spectroscopy and microscopic imaging of stratum corneum models and skin. Phys Chem Chem Phys. 2000;2(20):4651–7.CrossRefGoogle Scholar
  44. 44.
    Garidel P. Calorimetric and spectroscopic investigations of phytosphingosine ceramide membrane organisation. Phys Chem Chem Phys. 2002;4:1934–42.CrossRefGoogle Scholar
  45. 45.
    Moore DJ, Rerek ME. Insights into the molecular organization of lipids in the skin barrier from infrared spectroscopy studies of stratum corneum lipid models. Acta Derm Venereol Suppl (Stockh). 2000;208:16–22.Google Scholar
  46. 46.
    Lin SY, Duan KJ, Lin TC. Microscopic FT-IR/DSC system used to simultaneously investigate the conversion process of protein structure in porcine stratum corneum after pretreatment with skin penetration enhancers. Meth Find Exp Clin Pharmacol. 1996;18(3):175–81.Google Scholar
  47. 47.
    Bommannan D, Potts RO, Guy RH. Examination of the effect of ethanol on human stratum corneum in vivo using infrared spectroscopy. J Control Release. 1991;16(3):299–304.CrossRefGoogle Scholar
  48. 48.
    Krill SL, Knutson K, Higuchi WI. Ethanol effects on the stratum corneum lipid phase behavior. Biochim Biophys Acta. 1992;1112(2):273–80.CrossRefPubMedGoogle Scholar
  49. 49.
    Krishnaiah YS, Satyanarayana V, Karthikeyan RS. Effect of the solvent system on the in vitro permeability of nicardipine hydrochloride through excised rat epidermis. J Pharm Pharm Sci. 2002;5(2):123–30.PubMedGoogle Scholar
  50. 50.
    Wotton PK, Møllgaard B, Hadgraft J, Hoelgaard A. Vehicle effect on topical drug delivery. III. Effect of azone on the cutaneous permeation of metronidazole and propylene glycol. Int J Pharm. 1985;24(1):19–26.CrossRefGoogle Scholar
  51. 51.
    Amin S, Kohli K, Khar RK, Mir SR, Pillai KK. Mechanism of in vitro percutaneous absorption enhancement of carvedilol by penetration enhancers. Pharm Dev Technol. 2008;13(6):533–9.CrossRefPubMedGoogle Scholar
  52. 52.
    Berner B, Mazzenga GC, Otte JH, Steffens RJ, Juang RH, Ebert CD. Ethanol: water mutually enhanced transdermal therapeutic system II: skin permeation of ethanol and nitroglycerin. J Pharm Sci. 1989;78(5):402–7.CrossRefPubMedGoogle Scholar
  53. 53.
    Levang AK, Zhao K, Singh J. 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. 1999;181(2):255–63.CrossRefPubMedGoogle Scholar
  54. 54.
    Song Y, Xiao C, Mendelsohn R, Zheng T, Strekowski L, Michniak B. Investigation of iminosulfuranes as novel transdermal penetration enhancers: enhancement activity and cytotoxicity. Pharm Res. 2005;22(11):1918–25.CrossRefPubMedGoogle Scholar
  55. 55.
    Greve T, Andersen K, Nielsen O. Penetration mechanism of dimethyl sulfoxide in human and pig ear skin: an ATR–FTIR and near-FT Raman spectroscopic in vivo and in vitro study. Spectrosc Int J. 2008;22(5):405–17.Google Scholar
  56. 56.
    Barry BW. Mode of action of penetration enhancers in human skin. J Control Release. 1987;6(1):85–97.CrossRefGoogle Scholar
  57. 57.
    Schneider A, Middaugh CR, Oldewurtel MD. Role of bound water in biological membrane structure: fluorescence and infrared studies. J Supramol Struct. 1979;10(2):265–75.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2010

Authors and Affiliations

  1. 1.Ernest Mario School of PharmacyRutgers—The State University of New JerseyPiscatawayUSA
  2. 2.New Jersey Center for BiomaterialsRutgers—The State University of New JerseyPiscatawayUSA

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