AAPS PharmSciTech

, Volume 14, Issue 1, pp 111–120 | Cite as

The Experimental Evaluation and Molecular Dynamics Simulation of a Heat-Enhanced Transdermal Delivery System

  • Daniel P. Otto
  • Melgardt M. de Villiers
Research Article


Transdermal delivery systems are useful in cases where preferred routes such as the oral route are not available. However, low overall extent of delivery is seen due to the permeation barrier posed by the skin. Chemical penetration enhancers and invasive methods that disturb the structural barrier function of the skin can be used to improve transdermal drug delivery. However, for suitable drugs, a fast-releasing transdermal delivery system can be produced by incorporating a heating source into a transdermal patch. In this study, a molecular dynamics simulation showed that heat increased the diffusivity of the drug molecules, resulting in faster release from gels containing ketoprofen, diclofenac sodium, and lidocaine HCl. Simulations were confirmed by in vitro drug release studies through lipophilic membranes. These correlations could expand the application of heated transdermal delivery systems for use as fast-release-dosage forms.


diffusion heated patch ketoprofen molecular dynamics transdermal 

Supplementary material

12249_2012_9900_MOESM1_ESM.docx (197 kb)
ESM 1 (DOCX 196 kb)
12249_2012_9900_MOESM2_ESM.avi (8.8 mb)
ESM 2 (AVI 9028 kb)


  1. 1.
    Pergolizzi JV, Philip BK, Leslie JB, Taylor R, Raffa RB. Perspectives on transdermal scopolamine for the treatment of postoperative nausea and vomiting. J Clin Anesth. 2012;24:334–45.PubMedCrossRefGoogle Scholar
  2. 2.
    Rao PR, Reddy MN, Ramakrishna S, Diwan PV. Comparative in vivo evaluation of propranolol hydrochloride after oral and transdermal administration in rabbits. Eur J Pharm Biopharm. 2003;56:81–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Walters KA, Brain KR, Green DM, James VJ, Watkinson AC, Sands RH. Comparison of the transdermal delivery of estradiol from two gel formulations. Maturitas. 1998;29:189–95.PubMedCrossRefGoogle Scholar
  4. 4.
    Xi H, Yang Y, Zhao D, Fang L, Sun L, Mu L, Lu J, Zhao N, Zhao Y, Zheng N, He Z. Transdermal patches for the site-specific delivery of anastrozole. In vitro and local tissue disposition evaluation. Int J Pharm. 2010;391:73–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Muktadir A, Barbar A, Cutie AJ, Plakogiannis FM. Medicament release from ointment bases. III. Ibuprofen: in vitro release and in-vivo absorption in rabbits. Drug Dev Ind Pharm. 1986;12:2521–40.CrossRefGoogle Scholar
  6. 6.
    Sammeta SM, Vaka SRK, Murthy SN. Transcutaneous electroporation mediated delivery of doxepin-HPCD complex: a sustained release approach for treatment of postherpetic neuralgia. J Control Release. 2010;142:361–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Ammar HO, Ghorab M, El-Nahhas SA, Kamel R. Design of a transdermal delivery system for aspirin as an antithrombotic drug. Int J Pharm. 2006;327:81–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Bouwstra JA, Honeywell-Nguyen PL. Skin structure and mode of action of vesicles. Adv Drug Deliv Rev. 2002;1(Supple 1):41–55.CrossRefGoogle Scholar
  9. 9.
    Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2004;56:603–18.PubMedCrossRefGoogle Scholar
  10. 10.
    Sullivan SP, Murthy N, Prausnitz MR. Minimally invasive protein delivery with rapidly dissolving polymer microneedles. Adv Mater. 2010;22:739–43.CrossRefGoogle Scholar
  11. 11.
    Prausnitz MR, Bose VG, Langer R, Weaver JC. Electroporation of mammalian skin: a mechanism to enhance transdermal drug delivery. Proc Natl Acad Sci USA. 1993;90:10504–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Lee WR, Shen SC, Wang KH, Hu CH, Fang JY. The effect of laser treatment on skin to enhance and control transdermal delivery of 5-fluorouracil. J Pharm Sci. 2002;91:1613–26.PubMedCrossRefGoogle Scholar
  13. 13.
    Kalia YN, Naik A, Garrison J, Guy RH. Iontophoretic drug delivery. Adv Drug Deliv Rev. 2004;56:619–58.PubMedCrossRefGoogle Scholar
  14. 14.
    Mitragotri S, Blankschtein D, Langer R. Ultrasound-mediated transdermal protein delivery. Science. 1995;269:850–3.PubMedCrossRefGoogle Scholar
  15. 15.
    Ashburn MA, Ogden LL, Zhang G, Love G, Basta SV. The pharmacokinetics of transdermal fentanyl delivered with and without controlled heat. J Pain. 2003;4:291–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Carter KA. Heat-associated increase in transdermal fentanyl absorption. Am J Health Syst Pharm. 2003;60:191–2.PubMedGoogle Scholar
  17. 17.
    Shomaker TS, Zhang J, Ashburn MA. A pilot study assessing the impact of heat on the transdermal delivery of testosterone. J Clin Pharmacol. 2001;41:677–82.PubMedCrossRefGoogle Scholar
  18. 18.
    Klemsdal TO, Gjesdal K, Bredesen JE. Heating and cooling of the nitroglycerin patch application area modify the plasma level of nitroglycerin. Eur J Clin Pharmacol. 1992;43:625–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Yun J, Lee DH, Im JS, Kim HI. Improvement in transdermal drug delivery by graphite oxide/temperature-responsive hydrogel composites with micro heater. J Mater Sci C. 2012;32:1564–70.CrossRefGoogle Scholar
  20. 20.
    Kim KS, Simon L. Modeling and design of transdermal drug delivery patches containing an external heating device. Comput Chem Eng. 2011;35:1152–63.CrossRefGoogle Scholar
  21. 21.
    Wood DG, Brown MC, Jones SA. Controlling barrier penetration via exothermic iron oxidation. Int J Pharm. 2011;404:42–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Nuvo Research Inc. (2012) Controlled heat-assisted drug delivery (CHADD™) technology. Accessed 16 August 2012.
  23. 23.
    Accelrys Software Inc. Materials Studio® 6.0 (2012) Accelrys Software Inc. San Diego, USA. Accessed 04 June 2012.
  24. 24.
    Hess B, Kutzner C, Van der Spoel D, Lindahl E. GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput. 2008;4:435–47.CrossRefGoogle Scholar
  25. 25.
    Plimpton S. Fast parallel algorithms for short-range molecular dynamics. J Comput Phys. 1995;117:1–19.CrossRefGoogle Scholar
  26. 26.
    Chaharati SG, Stern SA. Diffusion of gases in silicone polymers: molecular dynamics simulations. Macromolecules. 1998;31:5529–38.CrossRefGoogle Scholar
  27. 27.
    Hofmann D, Fritz L, Ulbrich J, Schepers C, Boehning M. Detailed-atomistic molecular modeling of small molecule diffusion and solution processes in polymeric membrane materials. Macromol Theor Simul. 2000;9:293–327.CrossRefGoogle Scholar
  28. 28.
    Gautieri A, Mezzanzanica A, Motta A, Redealli A, Vesentini S. Atomistic modeling of water diffusion in hydrolytic biomaterials. J Mol Model. 2012;18:1495–502.PubMedCrossRefGoogle Scholar
  29. 29.
    Gautieri A, Vesentini S, Redaelli A. How to predict diffusion of medium-sized molecules in polymer matrices. From atomistic to coarse grain simulations. J Mol Model. 2010;16:1845–51.PubMedCrossRefGoogle Scholar
  30. 30.
    Dumortier G, Grossiord JL, Agnely F, Chaumeil JC. A review of poloxamer 407 pharmaceutical and pharmacological characteristics. Pharm Res. 2006;23:2709–28.PubMedCrossRefGoogle Scholar
  31. 31.
    Verlet L. Computer experiments on classical fluids. I. Thermodynamical properties of Lennard-Jones molecules. Phys Rev. 1967;159:98–103.CrossRefGoogle Scholar
  32. 32.
    Sun H. COMPASS: An ab initio force-field optimized for condensed-phase applications—overview with details on alkane and benzene compounds. J Phys Chem B. 1998;102:7338–64.CrossRefGoogle Scholar
  33. 33.
    Sun H, Rigby D. Polysiloxanes: ab initio forcefield and structural, conformational and thermophysical properties. Spectrochim Acta A. 1997;53:1301–23.CrossRefGoogle Scholar
  34. 34.
    Spyriouni T, Vergelati C. A molecular modeling study of binary blend compatibility of polyamide 6 and poly(vinyl acetate) with different degrees of hydrolysis: an atomistic and mesoscopic approach. Macromolecules. 2001;34:5306–16.CrossRefGoogle Scholar
  35. 35.
    Vetter T, Mazzotti M, Bronzio J. Slowing the growth rate of ibuprofen crystals using the polymeric additive Pluronic F127. Cryst Growth Des. 2011;11:3813–21.CrossRefGoogle Scholar
  36. 36.
    Ewald PP. Die Berechnung optischer und elektrostatischer Gitterpotentiale (evaluation of optical and electrostatic lattice potentials). Ann Phys. 1921;64:253–87.CrossRefGoogle Scholar
  37. 37.
    Berendsen HJC, Postma JPM, van Gunsteren WF, DiNola A, Haak JR. Molecular dynamics with coupling to an external bath. J Chem Phys. 1984;81:3684–90.CrossRefGoogle Scholar
  38. 38.
    \Andersen HC. Molecular dynamics simulations at constant pressure and/or temperature. J Chem Phys. 1980;72:2384–93.CrossRefGoogle Scholar
  39. 39.
    BASF (2012) Technical bulletin. Pluronics® F127 block copolymer surfactant. Available from: Accessed 16 August 2012.
  40. 40.
    Hofmann D, Fritz L, Ulbrich J, Paul UD. Molecular simulation of small molecule diffusion and solution in dense amorphous polysiloxanes and polyimides. Comput Theor Polym Sci. 2000;10:419–36.CrossRefGoogle Scholar
  41. 41.
    Theodorou DN, Suter UW. Detailed molecular structure of a vinyl polymer glass. Macromolecules. 1985;18:1467–78.CrossRefGoogle Scholar
  42. 42.
    Einstein A. Von der molekulärkinetischen Theorie der Wärme gefordete Bewegung von in ruhenden Flüssigkeiten suspendierten Teilchen (The motion of elements suspended in static liquids as claimed in the molecular kinetic theory of heat). Ann Phys. 1905;17:549–60.CrossRefGoogle Scholar
  43. 43.
    Liebenberg W, Engelbrecht E, Wessels A, Devarakonda B, Yang W, de Villiers MM. A comparative study of the release of active ingredients from semi-solid cosmeceuticals measured with a Franz, enhancer or flow-through cell diffusion apparatus. J Food Drug Anal (Yaowu Shipin Fenxi). 2004;12:19–28.Google Scholar
  44. 44.
    Tanaka K. Self-diffusion coefficients of water in pure water and in aqueous solutions of several electrolytes with 18O and 2H as tracers. J Chem Soc Faraday Trans 1 Phys Chem Condensed Phases. 1978;74:1879–81.Google Scholar
  45. 45.
    Arrhenius S. On the reaction velocity of the inversion of cane sugar by acids. Z Phys Chem. 1889;4:226.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2012

Authors and Affiliations

  1. 1.Catalysis and Synthesis Research Group, Chemical Resource Beneficiation Focus Area, Faculty of Natural SciencesNorth-West UniversityPotchefstroomSouth Africa
  2. 2.School of PharmacyUniversity of Wisconsin-MadisonMadisonUSA

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