The combination of microneedles with electroporation and sonophoresis to enhance hydrophilic macromolecule skin penetration

Abstract

The objective of the present work was to investigate the effects of 3 combinatorial techniques (microneedle (MN), electroporation (EP), and sonophoresis (SN)) on the in vitro skin permeation of the hydrophilic macromolecular compound fluorescein isothiocyanate-dextran (FD-4; M.W. 4.4 kDa). Assessment of the in vitro skin permeation of FD-4 was performed in porcine skin. MN, EP, and SN were used as physical enhancement methods, given the potential of their various mechanisms. The total cumulative amount of FD-4 that permeated through treated skin using 2 or 3 combined methods, i.e., MN+EP, MN+SN, EP+SN, and MN+EP+SN, was investigated. Microconduits created by MN alone and in combination with the other techniques were observed under confocal laser scanning microscopy (CLSM). The histology of the treated skin was examined. In vitro skin permeation experiments revealed that the total cumulative amount of FD-4 that permeated porcine skin using 3 combined techniques (MN+EP+SN) was greater than the amount observed using a single method or 2 combinations (MN+EP, MN+SN, SN+EP). The histological images indicate no noticeable damage in the skin treated with all of the enhancement methods. These results suggest that MN+EP+SN may serve as a potentially effective combination strategy to transdermally deliver various hydrophilic macromolecules without causing structural alterations or skin damage.

References

• 1) Hadgraft J: Skin, the final frontier. Int J Pharm, 224, 1–18 (2001).
• 2) Herwadkar A, Banga AK: Peptide and protein transdermal drug delivery. Drug Discovery Today, 9, e147–e154 (2012).
• 3) Foldvari: Non-invasive administration of drugs through the skin: challenges in delivery system design. Pharm Sci Technol Today, 3, 417–425 (2000).
• 4) Barry BW: Novel mechanisms and devices to enable successful transdermal drug delivery. Eur J Pharm Sci, 14, 101–114 (2001).
• 5) Prausnitz MR: Microneedles for transdermal drug delivery. Adv Drug Delivery Rev, 56, 581–587 (2004).
• 6) Tuan-Mahmood TM, McCrudden MTC, Torrisi BM, McAlister E, Garland MJ, Singh TRR: Microneedles for intradermal and transdermal drug delivery. Eur J Pharm Sci, 50, 623–637 (2013).
• 7) Denet AR, Vanbever R, Préat V: Skin electroporation for transdermal and topical delivery. Adv Drug Delivery Rev, 56, 659–674(2004).
• 8) Denet AR, Préat V: Transdermal delivery of timolol by electroporation through human skin. J Controlled Release, 88, 253–262 (2003).
• 9) Chang SL, Hofmann GA, Zhang L, Deftos LJ, Banga AK: The effect of electroporation on iontophoretic transdermal delivery of calcium regulating hormones. J Controlled Release, 66, 127–133 (2000).
• 10) Medi BM, Singh J: Electronically facilitated transdermal delivery of human parathyroid hormone (1-34). Int J Pharm, 263, 25–33 (2003).
• 11) Tokudome Y, Sugibayashi K: The effects of calcium chloride and sodium chloride on the electroporation-mediated skin permeation of fluorescein isothiocyanate (FITC)-dextrans in vitro. Biol Pharm Bull, 26, 1508–1510 (2003).
• 12) Guo S, Donate A, Basu G, Lundberg C, Heller L, Heller R: Electro-gene transfer to skin using a noninvasive multielectrode array. J Controlled Release, 151, 256–262 (2011).
• 13) Meidan VM, Walmsley AD, Irwin WJ: Phonophoresis - is it a reality? Int J Pharm, 118, 129–149 (1995).
• 14) Park D, Park H, Seo J, Lee S: Sonophoresis in transdermal drug deliverys. Ultrasonics, 54, 56–65 (2014).
• 15) Polat BE, Hart D, Langer R, Blankschtein D: Ultrasound-mediated transdermal drug delivery: mechanisms, scope, and emerging trends. J Controlled Release, 152,330–348 (2011).
• 16) Wu X-M, Todo H, Sugibayashi K: Enhancement of skin permeation of high molecular compounds by a combination of microneedle pretreatment and iontophoresis. J Controlled Release, 118, 189–195 (2007).
• 17) Kumar V, Banga AK: Modulated iontophoretic delivery of small and large molecules through microchannels. Int J Pharm, 434, 106–114 (2012).
• 18) Garland MJ, Caffarel–Salvador E, Migalska K, Woolfson AD, Donnelly RF: Dissolving polymeric microneedle arrays for electrically assisted transdermal drug delivery. J Controlled Release, 159, 52–59 (2012).
• 19) Yan K, Todo H, Sugibayashi K: Transdermal drug delivery by in-skin electroporation using a microneedle array. Int J Pharm, 397, 77–83 (2010).
• 20) Chen B, Wei J, Iliescu C: Sonophoretic enhanced microneedles array (SEMA)—Improving the efficiency of transdermal drug delivery. Sens Actuators B, 145, 54–60 (2010).
• 21) Godin B, Touitou E: Transdermal skin delivery: predictions for humans from in vivo, ex vivo and animal models. Adv Drug Delivery Rev, 59, 1152–1161 (2007).
• 22) Yamashita F, Hashida M: Mechanistic and empirical modeling of skin permeation of drugs. Adv Drug Delivery Rev, 55, 1185–1199 (2003).
• 23) Milewski M, Brogden NK, Stinchcomb AL: Current aspects of formulation efforts and pore lifetime related to microneedle treatment of skin. Expert Opin Drug Delivery, 7, 617–629 (2010).
• 24) Bhatt B, Koland M, Shama KP: Investigation of the ex vivo and in vivo iontophoretic delivery of aceclofenac from topical gels in Albino rats. Int J Pharm Invest, 3, 105–111 (2013).
• 25) Sung KC, Fang J-Y, Wang J-J, Hu OY-P: Transdermal delivery of nalbuphine and its prodrugs by electroporation. Eur J Pharm Sci, 18, 63–70 (2003).
• 26) Tezel A, Sens A, Tuchscherer J, Mitragotri S: Frequency dependence of sonophoresis. Pharm Res, 18, 1694–1700 (2001).
• 27) Boucaud A, Garrigue MA, Machet L, Vaillant L, Patat F: Effect of sonication parameters on transdermal delivery of insulin to hairless rats. J Controlled Release, 81, 113–119 (2002).
• 28) Lombry C, Dujardin N, Préat V: Transdermal delivery of macromolecules using skin electroporation. Pharm Res, 17, 32–37 (2000).
• 29) Alvarez-Román R, Naik A, Kalia Y, Fessi H, Guy R: Visualization of skin penetration using confocal laser scanning microscopy. Eur J Pharm Biopharm, 58, 301–316 (2004).
• 30) Menon GK, Cleary GW, Lane ME: The structure and function of the stratum corneum. Int J Pharm, 435, 3–9 (2012).
• 31) Naik A, Kalia YN, Guy RH: Transdermal drug delivery: overcoming the skin’s barrier function. Pharm Sci Technol Today, 3, 318–326 (2000).
• 32) Henry S, McAllister DV, Allen MG, Prausnitz MR: Microfabricated microneedles: a novel approach to transdermal drug delivery. J Pharm Sci. 87, 922–925 (1998).
• 33) Noh Y-W, Kim T-H, Baek J-S, Park H-H, Lee SS, Han M : In vitro characterization of the invasiveness of polymer microneedle against skin. Int J Pharm, 397, 201–205 (2010).
• 34) Martanto W, Moore JS, Couse T, Prausnitz MR. Mechanism of fluid infusion during microneedle insertion and retraction. J Control Release, 112, 357–361 (2006).
• 35) Verbaan FJ, Bal SM, van den Berg DJ, Dijksman JA, van Hecke M, Verpoorten H, et al. Improved piercing of microneedle arrays in dermatomed human skin by an impact insertion method. J Control Release, 128, 80–88 (2008).
• 36) Yan G, Warner KS, Zhang J, Sharma S, Gale BK. Evaluation needle length and density of microneedle arrays in the pretreatment of skin for transdermal drug delivery. Int J Pharm, 391, 7–12 (2010).
• 37) Teo MAL, Shearwood C, Ng KC, Lu J, Moochhala S. In vitro and in vivo characterization of MEMS microneedles. Biomed Microdevices, 7, 47–52 (2005).
• 38) Wermeling DP, Banks SL, Hudson DA, Gill HS, Gupta J, Prausnitz MR. Microneedles permit transdermal delivery of a skin-impermeant medication to humans. Proc Natl Acad Sci, 105, 2058–2063 (2008).
• 39) Wei-Ze L, Mei-Rong H, Jian-Ping Z, Yong-Qiang Z, Bao-Hua H, Ting L: Super-short solid silicon microneedles for transdermal drug delivery applications. Int J Pharm, 389, 122–129 (2010).
• 40) Park J-H, Allen MG, Prausnitz MR: Biodegradable polymer microneedles: Fabrication, mechanics and transdermal drug delivery. J Controlled Release, 104, 51–66 (2005).
• 41) Coulman SA, Anstey A, Gateley C, Morrissey A, McLoughlin P, Allender C: Microneedle mediated delivery of nanoparticles into human skin. Int J Pharm, 366, 190–200 (2009).
• 42) Kaur M, Ita KB, Popova IE, Parikh SJ, Bair DA: Microneedle-assisted delivery of verapamil hydrochloride and amlodipine besylate. Eur J Pharm Biopharm, 86, 284-291 (2014).
• 43) Zhang W, Gao J, Zhu Q, Zhang M, Ding X, Wang X, Hou X, Fan W, Ding B, Wu X, Wang X, Gao S: Penetration and distribution of PLGA nanoparticles in the human skin treated with microneedles. Int J Pharm, 402, 205–212, (2010).
• 44) Vanbever R, Préat V: Factors affecting transdermal delivery of metoprolol by electroporation. Bioelectrochem Bioenerg, 38, 223–228 (1995).
• 45) Zewert TE, Pliquett UF, Langer R, Weaver JC: Transdermal transport of DNA antisense oligonucleotides by electroporation. Biochem Biophys Res Commun, 212, 286–292 (1995).
• 46) Prausnitz MR: Do high-voltage pulses cause changes in skin structure? J Controlled Release, 40, 321–326 (1996).
• 47) Wolloch L, Kost J: The importance of microjet vs shock wave formation in sonophoresis. J Controlled Release. 148, 204–211 (2010).
• 48) Tezel A, Mitragotri S: Interactions of inertial cavitation bubbles with stratum corneum lipid bilayers during low-frequency sonophoresis. Biophys J, 85, 3502–3512 (2003).
• 49) Dujardin N, Staes E, Kalia Y, Clarys P, Guy R, Préat V: In vivo assessment of skin electroporation using square wave pulses. J Controlled Release, 79, 219–227 (2002).
• 50) Stahl J, Wohlert M, Kietzmann M: Microneedle pretreatment enhances the percutaneous permeation of hydrophilic compounds with high melting points. BMC Pharmacol Toxicol, 13, 1–7 (2012).
• 51) Blagus T, Markelc B, Cemazar M, Kosjek T, Preat V, Miklavcic D, Sersa G. :In vivo real-time monitoring system of electroporation mediated control of transdermal and topical drug delivery. J Controlled Release, 172, 862–871 (2013).