Fabrication and characterization of hyaluronic acid microneedles to enhance delivery of magnesium ascorbyl phosphate into skin

Abstract

This study investigated the in vitro transdermal delivery of magnesium ascorbyl phosphate (MAP) through porcine ear skin treated with hyaluronic acid (HA) microneedles (MNs). In this study, the micro-molding method was used to fabricate HA MNs. HA solution (10% w/v) containing 3% of MAP was placed onto a poly(dimethyl siloxane) mold to fill the microchannels under vacuum followed by drying in a desiccator. Scanning electron microscopy was performed to record the dimensions of the MNs. Skin microporation was demonstrated by dye binding. Histological skin sections revealed the shape of microchannels under hematoxylin-eosin staining. The actual depth of the microchannels and drug distribution pathways were studied by confocal microscopy. In vitro permeation on Franz diffusion cells were performed to determine the rate and extent of drug delivery into and across the skin. SEM captured individual MNs from the array, and the length of each MN was found to be ~400 μm. The 10 × 10 MN array prepared, resulted in the formation of 95 to 100 microchannels after 2 mins of treatment. In addition, the histological evaluations showed the formation of microchannels in the skin, complementary in shape to the MNs. The depths of the formed microchannels amounted to ~125 μm as determined by confocal microscopy. The application of the current MN technology enhanced the delivery of MAP into skin (96.8 ± 3.9 μg/cm2) compared to the passive delivery strategy of MAP (44.9 ± 16.3 μg/cm2). HA MNs markedly enhanced the in vitro transdermal delivery of MAP into and across skin.

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References

  1. S.M. Bal, A.C. Kruithof, R. Zwier, E. Dietz, J.A. Bouwstra, J. Lademann, M.C. Meinke, Influence of microneedle shape on the transport of a fluorescent dye into human skin in vivo. J. Control. Release 147, 218–224 (2010)

    Google Scholar 

  2. M. Campos, Histopathological, morphometric and stereological studies of ascorbic acid and magnesium ascorbyl phosphate in a skin care formulation. Int. J. Cosmet. Sci. 22, 169–179 (2000)

    Google Scholar 

  3. M. Chen, V. Gupta, A.C. Anselmo, J.A. Muraski, S. Mitragotri, Topical delivery of hyaluronic acid into skin using SPACE-peptide carriers. J. Control. Release 173, 67–74 (2014)

    Google Scholar 

  4. M. Dangol, S. Kim, C.G. Li, S.F. Lahiji, M. Jang, Y. Ma, I. Huh, H. Jung, Anti-obesity effect of a novel caffeine-loaded dissolving microneedle patch in high-fat diet-induced obese C57BL/6J mice. J. Control. Release265, 41–47 (2017)

    Google Scholar 

  5. P.C. DeMuth, A.V. Li, P. Abbink, J. Liu, H. Li, K.A. Stanley, K.M. Smith, C.L. Lavine, M.S. Seaman, J.A. Kramer, Vaccine delivery with microneedle skin patches in nonhuman primates. Nat. Biotechnol. 31, 1082 (2013)

    Google Scholar 

  6. R.F. Donnelly, R. Majithiya, T.R.R. Singh, D.I. Morrow, M.J. Garland, Y.K. Demir, K. Migalska, E. Ryan, D. Gillen, C.J. Scott, Design, optimization and characterisation of polymeric microneedle arrays prepared by a novel laser-based micromoulding technique. Pharm. Res. 28, 41–57 (2011)

    Google Scholar 

  7. R.F. Donnelly, D.I. Morrow, T.R. Singh, K. Migalska, P.A. McCarron, C. O'Mahony, A.D. Woolfson, Processing difficulties and instability of carbohydrate microneedle arrays. Drug Dev. Ind. Pharm. 35, 1242–1254 (2009)

    Google Scholar 

  8. R.F. Donnelly, T.R.R. Singh, M.J. Garland, K. Migalska, R. Majithiya, C.M. McCrudden, P.L. Kole, T.M.T. Mahmood, H.O. McCarthy, A.D. Woolfson, Hydrogel-forming microneedle arrays for enhanced transdermal drug delivery. Adv. Funct. Mater. 22, 4879–4890 (2012)

    Google Scholar 

  9. J.C. Geesin, J.S. Gordon, R.A. Berg, Regulation of collagen synthesis in human dermal fibroblasts by the sodium and magnesium salts of ascorbyl-2-phosphate. Skin Pharmacol. Physiol. 6, 65–71 (1993)

    Google Scholar 

  10. H.S. Gill, M.R. Prausnitz, Coating formulations for microneedles. Pharm. Res. 24, 1369–1380 (2007)

    Google Scholar 

  11. S.D. Gittard, A. Ovsianikov, B.N. Chichkov, A. Doraiswamy, R.J. Narayan, Two-photon polymerization of microneedles for transdermal drug delivery. Expert Opin. Drug Deliv. 7, 513–533 (2010)

    Google Scholar 

  12. M. Han, D.K. Kim, S.H. Kang, H.-R. Yoon, B.-Y. Kim, S.S. Lee, K.D. Kim, H.G. Lee, Improvement in antigen-delivery using fabrication of a grooves-embedded microneedle array. Sensors Actuators B Chem. 137, 274–280 (2009)

    Google Scholar 

  13. M. Haq, E. Smith, D.N. John, M. Kalavala, C. Edwards, A. Anstey, A. Morrissey, J.C. Birchall, Clinical administration of microneedles: skin puncture, pain and sensation. Biomed. Microdevices 11, 35–47 (2009)

    Google Scholar 

  14. S. Henry, D.V. McAllister, M.G. Allen, M.R. Prausnitz, Microfabricated microneedles: a novel approach to transdermal drug delivery. J. Pharm. Sci. 87, 922–925 (1998)

    Google Scholar 

  15. S. Hirobe, H. Azukizawa, T. Hanafusa, K. Matsuo, Y.S. Quan, F. Kamiyama, I. Katayama, N. Okada, S. Nakagawa, Clinical study and stability assessment of a novel transcutaneous influenza vaccination using a dissolving microneedle patch. Biomaterials 57, 50–58 (2015)

    Google Scholar 

  16. W.W.-Y. Kao, J.G. Flaks, D.J. Prockop, Primary and secondary effects of ascorbate on procollagen synthesis and protein synthesis by primary cultures of tendon fibroblasts. Arch. Biochem. Biophys. 173, 638–648 (1976)

    Google Scholar 

  17. Y.C. Kim, J.H. Park, M.R. Prausnitz, Microneedles for drug and vaccine delivery. Adv. Drug Deliv. Rev. 64, 1547–1568 (2012)

    Google Scholar 

  18. S. Lau, J. Fei, H. Liu, W. Chen, R. Liu, Multilayered pyramidal dissolving microneedle patches with flexible pedestals for improving effective drug delivery. J. Control. Release 265, 113–119 (2017)

    Google Scholar 

  19. J.W. Lee, J.H. Park, M.R. Prausnitz, Dissolving microneedles for transdermal drug delivery. Biomaterials 29, 2113–2124 (2008)

    Google Scholar 

  20. W.-R. Lee, S.-C. Shen, K.-H. Wang, C.-H. Hu, J.-Y. Fang, Lasers and microdermabrasion enhance and control topical delivery of vitamin C. J. Investig. Dermatol. 121, 1118–1125 (2003)

    Google Scholar 

  21. W. Li, R.N. Terry, J. Tang, M.R. Feng, S.P. Schwendeman, M.R. Prausnitz, Rapidly separable microneedle patch for the sustained release of a contraceptive. Nat. Biomed. Eng. 3, 220–229 (2019)

    Google Scholar 

  22. S. Liu, D. Wu, Y.S. Quan, F. Kamiyama, K. Kusamori, H. Katsumi, T. Sakane, A. Yamamoto, Improvement of transdermal delivery of Exendin-4 using novel tip-loaded microneedle arrays fabricated from hyaluronic acid. Mol. Pharm.13, 272–279 (2016)

    Google Scholar 

  23. P.M.B.G. Maia Campos, F.B. de Camargo Júnior, J.P. de Andrade, L.R. Gaspar, Efficacy of cosmetic formulations containing dispersion of liposome with magnesium ascorbyl phosphate, alpha-lipoic acid and kinetin. Photochem. Photobiol. 88, 748–752 (2012)

    Google Scholar 

  24. W. Martanto, S.P. Davis, N.R. Holiday, J. Wang, H.S. Gill, M.R. Prausnitz, Transdermal delivery of insulin using microneedles in vivo. Pharm. Res. 21, 947–952 (2004)

    Google Scholar 

  25. W. Martanto, J.S. Moore, T. Couse, M.R. Prausnitz, Mechanism of fluid infusion during microneedle insertion and retraction. J. Control. Release112, 357–361 (2006)

    Google Scholar 

  26. D.V. McAllister, P.M. Wang, S.P. Davis, J.H. Park, P.J. Canatella, M.G. Allen, M.R. Prausnitz, Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: fabrication methods and transport studies. Proc. Natl. Acad. Sci. U. S. A. 100, 13755–13760 (2003)

    Google Scholar 

  27. M.G. McGrath, S. Vucen, A. Vrdoljak, A. Kelly, C. O'Mahony, A.M. Crean, A. Moore, Production of dissolvable microneedles using an atomised spray process: effect of microneedle composition on skin penetration. Eur. J. Pharm. Biopharm. 86, 200–211 (2014)

    Google Scholar 

  28. H.X. Nguyen, A.K. Banga, Enhanced skin delivery of vismodegib by microneedle treatment. Drug Deliv. Transl. Res. 5, 407–423 (2015)

    Google Scholar 

  29. H.X. Nguyen, A.K. Banga, Delivery of methotrexate and characterization of skin treated by fabricated PLGA microneedles and fractional ablative laser. Pharm. Res. 35, 68 (2018)

    Google Scholar 

  30. H.X. Nguyen, B.D. Bozorg, Y. Kim, A. Wieber, G. Birk, D. Lubda, A.K. Banga, Poly (vinyl alcohol) microneedles: fabrication, characterization, and application for transdermal drug delivery of doxorubicin. Eur. J. Pharm. Biopharm. 129, 88–103 (2018)

    Google Scholar 

  31. J. Pan, W. Ruan, M. Qin, Y. Long, T. Wan, K. Yu, Y. Zhai, C. Wu, Y. Xu, Intradermal delivery of STAT3 siRNA to treat melanoma via dissolving microneedles. Sci. Rep. 8, 1117 (2018)

    Google Scholar 

  32. E. Papakonstantinou, M. Roth, G. Karakiulakis, Hyaluronic acid: a key molecule in skin aging. Dermato-endocrinology 4, 253–258 (2012)

    Google Scholar 

  33. J.H. Park, M.G. Allen, M.R. Prausnitz, Polymer microneedles for controlled-release drug delivery. Pharm. Res. 23, 1008–1019 (2006)

    Google Scholar 

  34. S.Y. Park, H.U. Lee, Y.C. Lee, G.H. Kim, E.C. Park, S.H. Han, J.G. Lee, S. Choi, N.S. Heo, D.L. Kim, Y.S. Huh, J. Lee, Wound healing potential of antibacterial microneedles loaded with green tea extracts. Materials science & engineering C. Mater. Biol. Appl. 42, 757–762 (2014)

    Google Scholar 

  35. Y. Park, J. Park, G.S. Chu, K.S. Kim, J.H. Sung, B. Kim, Transdermal delivery of cosmetic ingredients using dissolving polymer microneedle arrays. Biotechnol. Bioprocess Eng. 20, 543–549 (2015)

    Google Scholar 

  36. F. Pérennès, B. Marmiroli, M. Matteucci, M. Tormen, L. Vaccari, E.D. Fabrizio, Sharp beveled tip hollow microneedle arrays fabricated by LIGA and 3D soft lithography with polyvinyl alcohol. J. Micromech. Microeng.16, 473–479 (2006)

    Google Scholar 

  37. F. Sammoura, J. Kang, Y.-M. Heo, T. Jung, L. Lin, Polymeric microneedle fabrication using a microinjection molding technique. Microsyst. Technol. 13, 517–522 (2007)

    Google Scholar 

  38. H.P. Tham, K. Xu, W.Q. Lim, H. Chen, M. Zheng, T.G.S. Thng, S.S. Venkatraman, C. Xu, Y. Zhao, Microneedle-assisted topical delivery of photodynamically active mesoporous formulation for combination therapy of deep-seated melanoma. ACS Nano 12, 11936–11948 (2018)

    Google Scholar 

  39. K. van der Maaden, W. Jiskoot, J. Bouwstra, Microneedle technologies for (trans)dermal drug and vaccine delivery. J. Control. Release161, 645–655 (2012)

    Google Scholar 

  40. M. Yang, J.D. Zahn, Microneedle insertion force reduction using vibratory actuation. Biomed. Microdevices 6, 177–182 (2004)

    Google Scholar 

  41. C. Zhang, K. Zhang, J. Zhang, H. Ou, J. Duan, S. Zhang, D. Wang, S. Mitragotri, M. Chen, Skin delivery of hyaluronic acid by the combined use of sponge spicules and flexible liposomes. Biomater. Sci. 7, 1299–1310 (2019)

    Google Scholar 

  42. Z. Zhu, H. Luo, W. Lu, H. Luan, Y. Wu, J. Luo, Y. Wang, J. Pi, C.Y. Lim, H. Wang, Rapidly dissolvable microneedle patches for transdermal delivery of exenatide. Pharm. Res. 31, 3348–3360 (2014)

    Google Scholar 

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Funding

This project was funded by Merck KGaA (Darmstadt, Germany). The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada. Product designations of Merck KGaA, Darmstadt, Germany and third parties may appear in this material. For details on the ownership of mentioned trademarks, please refer to publicly available resources like tmdn.org.

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Correspondence to Ajay K. Banga.

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Kim, Y., Bhattaccharjee, S.A., Beck-Broichsitter, M. et al. Fabrication and characterization of hyaluronic acid microneedles to enhance delivery of magnesium ascorbyl phosphate into skin. Biomed Microdevices 21, 104 (2019). https://doi.org/10.1007/s10544-019-0455-0

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Keywords

  • Microfabrication
  • Transdermal drug delivery
  • Dissolving microneedle
  • Hydrophilic drug
  • Hyaluronic acid