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

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Abstract

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.

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REFERENCES

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  8. Bouwstra JA, Honeywell-Nguyen PL. Skin structure and mode of action of vesicles. Adv Drug Deliv Rev. 2002;1(Supple 1):41–55.

    Article  Google Scholar 

  9. Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2004;56:603–18.

    Article  PubMed  CAS  Google Scholar 

  10. Sullivan SP, Murthy N, Prausnitz MR. Minimally invasive protein delivery with rapidly dissolving polymer microneedles. Adv Mater. 2010;22:739–43.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  13. Kalia YN, Naik A, Garrison J, Guy RH. Iontophoretic drug delivery. Adv Drug Deliv Rev. 2004;56:619–58.

    Article  PubMed  CAS  Google Scholar 

  14. Mitragotri S, Blankschtein D, Langer R. Ultrasound-mediated transdermal protein delivery. Science. 1995;269:850–3.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  16. Carter KA. Heat-associated increase in transdermal fentanyl absorption. Am J Health Syst Pharm. 2003;60:191–2.

    PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  21. Wood DG, Brown MC, Jones SA. Controlling barrier penetration via exothermic iron oxidation. Int J Pharm. 2011;404:42–8.

    Article  PubMed  CAS  Google Scholar 

  22. Nuvo Research Inc. (2012) Controlled heat-assisted drug delivery (CHADD™) technology. http://www.nuvoresearch.com/research/chadd.htm. Accessed 16 August 2012.

  23. Accelrys Software Inc. Materials Studio® 6.0 (2012) Accelrys Software Inc. San Diego, USA. http://www.accelrys.com. Accessed 04 June 2012.

  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.

    Article  CAS  Google Scholar 

  25. Plimpton S. Fast parallel algorithms for short-range molecular dynamics. J Comput Phys. 1995;117:1–19.

    Article  CAS  Google Scholar 

  26. Chaharati SG, Stern SA. Diffusion of gases in silicone polymers: molecular dynamics simulations. Macromolecules. 1998;31:5529–38.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  30. Dumortier G, Grossiord JL, Agnely F, Chaumeil JC. A review of poloxamer 407 pharmaceutical and pharmacological characteristics. Pharm Res. 2006;23:2709–28.

    Article  PubMed  CAS  Google Scholar 

  31. Verlet L. Computer experiments on classical fluids. I. Thermodynamical properties of Lennard-Jones molecules. Phys Rev. 1967;159:98–103.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  33. Sun H, Rigby D. Polysiloxanes: ab initio forcefield and structural, conformational and thermophysical properties. Spectrochim Acta A. 1997;53:1301–23.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  36. Ewald PP. Die Berechnung optischer und elektrostatischer Gitterpotentiale (evaluation of optical and electrostatic lattice potentials). Ann Phys. 1921;64:253–87.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  38. \Andersen HC. Molecular dynamics simulations at constant pressure and/or temperature. J Chem Phys. 1980;72:2384–93.

    Article  CAS  Google Scholar 

  39. BASF (2012) Technical bulletin. Pluronics® F127 block copolymer surfactant. Available from: http://worldaccount.basf.com/wa/NAFTA/Catalog/ChemicalsNAFTA/doc4/BASF/PRD/30089187. Accessed 16 August 2012.

  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.

    Article  CAS  Google Scholar 

  41. Theodorou DN, Suter UW. Detailed molecular structure of a vinyl polymer glass. Macromolecules. 1985;18:1467–78.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  45. Arrhenius S. On the reaction velocity of the inversion of cane sugar by acids. Z Phys Chem. 1889;4:226.

    Google Scholar 

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Correspondence to Melgardt M. de Villiers.

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Otto, D.P., de Villiers, M.M. The Experimental Evaluation and Molecular Dynamics Simulation of a Heat-Enhanced Transdermal Delivery System. AAPS PharmSciTech 14, 111–120 (2013). https://doi.org/10.1208/s12249-012-9900-6

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