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
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.
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.
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.
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.
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.
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.
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.
Bouwstra JA, Honeywell-Nguyen PL. Skin structure and mode of action of vesicles. Adv Drug Deliv Rev. 2002;1(Supple 1):41–55.
Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2004;56:603–18.
Sullivan SP, Murthy N, Prausnitz MR. Minimally invasive protein delivery with rapidly dissolving polymer microneedles. Adv Mater. 2010;22:739–43.
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.
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.
Kalia YN, Naik A, Garrison J, Guy RH. Iontophoretic drug delivery. Adv Drug Deliv Rev. 2004;56:619–58.
Mitragotri S, Blankschtein D, Langer R. Ultrasound-mediated transdermal protein delivery. Science. 1995;269:850–3.
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.
Carter KA. Heat-associated increase in transdermal fentanyl absorption. Am J Health Syst Pharm. 2003;60:191–2.
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.
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.
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.
Kim KS, Simon L. Modeling and design of transdermal drug delivery patches containing an external heating device. Comput Chem Eng. 2011;35:1152–63.
Wood DG, Brown MC, Jones SA. Controlling barrier penetration via exothermic iron oxidation. Int J Pharm. 2011;404:42–8.
Nuvo Research Inc. (2012) Controlled heat-assisted drug delivery (CHADD™) technology. http://www.nuvoresearch.com/research/chadd.htm. Accessed 16 August 2012.
Accelrys Software Inc. Materials Studio® 6.0 (2012) Accelrys Software Inc. San Diego, USA. http://www.accelrys.com. Accessed 04 June 2012.
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.
Plimpton S. Fast parallel algorithms for short-range molecular dynamics. J Comput Phys. 1995;117:1–19.
Chaharati SG, Stern SA. Diffusion of gases in silicone polymers: molecular dynamics simulations. Macromolecules. 1998;31:5529–38.
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.
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.
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.
Dumortier G, Grossiord JL, Agnely F, Chaumeil JC. A review of poloxamer 407 pharmaceutical and pharmacological characteristics. Pharm Res. 2006;23:2709–28.
Verlet L. Computer experiments on classical fluids. I. Thermodynamical properties of Lennard-Jones molecules. Phys Rev. 1967;159:98–103.
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.
Sun H, Rigby D. Polysiloxanes: ab initio forcefield and structural, conformational and thermophysical properties. Spectrochim Acta A. 1997;53:1301–23.
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.
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.
Ewald PP. Die Berechnung optischer und elektrostatischer Gitterpotentiale (evaluation of optical and electrostatic lattice potentials). Ann Phys. 1921;64:253–87.
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.
\Andersen HC. Molecular dynamics simulations at constant pressure and/or temperature. J Chem Phys. 1980;72:2384–93.
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.
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.
Theodorou DN, Suter UW. Detailed molecular structure of a vinyl polymer glass. Macromolecules. 1985;18:1467–78.
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.
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.
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.
Arrhenius S. On the reaction velocity of the inversion of cane sugar by acids. Z Phys Chem. 1889;4:226.
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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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DOI: https://doi.org/10.1208/s12249-012-9900-6