AAPS PharmSciTech

, 20:215 | Cite as

Fabrication of Dissolvable Microneedle Patches Using an Innovative Laser-Cut Mould Design to Shortlist Potentially Transungual Delivery Systems: In Vitro Evaluation

  • Esra’a AlbarahmiehEmail author
  • Labiba AbuAmmouneh
  • Zaina Kaddoura
  • Farah AbuHantash
  • Bashar A. Alkhalidi
  • Alaaldeen Al-Halhouli
Research Article


There has been a great interest towards transungual delivery systems due to limited drug penetration for the treatment of nail diseases. More important, antifungal oral medicaments used may cause serious side effects including liver damage. Therefore, we propose non-oral dissolvable microneedle (MN) patch to strike the poor permeability of the nail. We report the design of MN patch mould using a laser-cutting machine and solvent casting of several hydrophilic polymers to fabricate these MN patches. Formulations were evaluated for their in vitro release and penetration properties and selected based on physical characterization for compatibility (differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD)), dimension repeatability and drug content uniformity. A 72-array of cone-shaped MN patch mould was successfully constructed on polymethylmethacrylate sheets. Interval and frequency of laser exposure were pivotal to determine the needle sharpness, attained unexpectedly at a low level of circa 30 μm. F1 platform of polyvinyl alcohol, kollicoat IR®, ethylene glycol and gelatin showed circa 74% penetration of methylhydroxy-4-benzoate (F1(A)) over 24 h, whereas F2 (same as F1-A with the addition of poloxamer 338) resulted in an almost 42% of this drug retention in the bovine hoof (24 h). Both formulations are likely to be useful for onychomycosis treatment. F1 polymers also afford enhanced permeability (almost 73.5% after 24 h) of terbinafine hydrochloride into the hoof (F1(B)). However, F3 (chitosan, gelatin and ethylene glycol) presents the prospect of developing MN patch for this drug with almost complete hoof penetration (circa 96.3% after 24 h). All medicated formulations have shown similar mechanical properties after ageing for 1 year under dry conditions.

Key Words

laser-cutting and engraving commands dissolvable microneedle patch hydrophilic polymers nail bovine hoof transungual delivery onychomycosis 



The authors would like to thank Engineer Baider Alhamarneh and Engineer Firas AlHindawi for their kind assistance.

Funding Information

The study was financially supported by the Deanship of Scientific Research (SAMS 16/2015) at the German Jordanian University.

Compliance with Ethical Standards

All institutional and national guidelines for the care and use of laboratory animals were followed.

Conflict of Interest

The authors declare that they have no conflict of interest.

All institutional and national guidelines for the care and use of laboratory animals were followed.


  1. 1.
    Elsayed M. Development of topical therapeutics for management of onychomycosis and other nail disorders: a pharmaceutical perspective. J Control Release. 2015;199:132–44.CrossRefGoogle Scholar
  2. 2.
    Ghannoum M, Hajjeh R, Scher R, Konnikov N, Gupta A, Summerbell R, et al. A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns. J Am Acad Dermatol. 2000;43(4):641–8.CrossRefGoogle Scholar
  3. 3.
    Kashyap B, Bhalla P, Kaur R. Onychomycosis—epidemiology, diagnosis and management. Indian J Med Microbiol. 2008;26(2):108.CrossRefGoogle Scholar
  4. 4.
    Saner M, Kulkarni A, Pardeshi C. Insights into drug delivery across the nail plate barrier. J Drug Target. 2014;22(9):769–89.CrossRefGoogle Scholar
  5. 5.
    Brown M, Khengar R, Turner R, Forbes B, Traynor M, Evans C, et al. Overcoming the nail barrier: a systematic investigation of ungual chemical penetration enhancement. Int J Pharm. 2009;370(1–2):61–7.CrossRefGoogle Scholar
  6. 6.
    Elewski B, Tavakkol A. Safety and tolerability of oral antifungal agents in the treatment of fungal nail disease: a proven reality. Ther Clin Risk Manag. 2005;1(4):299–306.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Murthy S, Maibach H. Topical nail products and ungual drug delivery. Boca Raton, FL: CRC Press; 2013.Google Scholar
  8. 8.
    Kim Y, Park J, Prausnitz M. Microneedles for drug and vaccine delivery. Adv Drug Deliv Rev. 2012;64(14):1547–68.CrossRefGoogle Scholar
  9. 9.
    Ono A, Ito S, Sakagami S, Asada H, Saito M, Quan Y, et al. Development of novel faster-dissolving microneedle patches for transcutaneous vaccine delivery. Pharmaceutics. 2017;9(4):27.CrossRefGoogle Scholar
  10. 10.
    Arya J, Henry S, Kalluri H, McAllister D, Pewin W, Prausnitz M. Tolerability, usability and acceptability of dissolving microneedle patch administration in human subjects. Biomaterials. 2017;128:1–7.CrossRefGoogle Scholar
  11. 11.
    Poirier D, Renaud F, Dewar V, Strodiot L, Wauters F, Janimak J, et al. Hepatitis B surface antigen incorporated in dissolvable microneedle array patch is antigenic and thermostable. Biomaterials. 2017;145:256–65.CrossRefGoogle Scholar
  12. 12.
    Ita K. Transdermal delivery of drugs with microneedles—potential and challenges. Pharmaceutics. 2015;7(3):90–105.CrossRefGoogle Scholar
  13. 13.
    Ita K. Transdermal delivery of drugs with microneedles: strategies and outcomes. J Drug Deliv Sci Technol. 2015;29:16–23.CrossRefGoogle Scholar
  14. 14.
    Lee J, Prausnitz M. Drug delivery using microneedle patches: not just for skin. Expert Opin Drug Deliv. 2018;15(6):541–3.CrossRefGoogle Scholar
  15. 15.
    Chouhan P, Saini T. Hydration of nail plate: a novel screening model for transungual drug permeation enhancers. Int J Pharm. 2012;436(1–2):179–82.CrossRefGoogle Scholar
  16. 16.
    Gunt H, Kasting G. Effect of hydration on the permeation of ketoconazole through human nail plate in vitro. Eur J Pharm Sci. 2007;32(4–5):254–60.CrossRefGoogle Scholar
  17. 17.
    Shivakumar H, Juluri A, Desai B, Murthy S. Ungual and transungual drug delivery. Drug Dev Ind Pharm. 2011;38(8):901–11.CrossRefGoogle Scholar
  18. 18.
    Khengar R, Jones S, Turner R, Forbes B, Brown M. Nail swelling as a pre-formulation screen for the selection and optimisation of ungual penetration enhancers. Pharm Res. 2007;24(12):2207–12.CrossRefGoogle Scholar
  19. 19.
    Scher R. Onychomycosis is more than a cosmetic problem. Br J Dermatol. 1994;130(s43):15.CrossRefGoogle Scholar
  20. 20.
    Dubini F, Bellotti M, Frangi A, Monti D, Saccomani L. In vitro antimycotic activity and nail permeation models of a piroctone olamine (Octopirox) containing transungual water soluble technology. Arzneimittelforschung. 2011;55(08):478–83.CrossRefGoogle Scholar
  21. 21.
    Monti D, Saccomani L, Chetoni P, Burgalassi S, Senesi S, Ghelardi E, et al. Hydrosoluble medicated nail lacquers: in vitro drug permeation and corresponding antimycotic activity. Br J Dermatol. 2010;162(2):311–7.CrossRefGoogle Scholar
  22. 22.
    Monti D, Saccomani L, Chetoni P, Burgalassi S, Tampucci S, Mailland F. Validation of bovine hoof slices as a model for infected human toenails: in vitro ciclopirox transungual permeation. Br J Dermatol. 2011;165(1):99–105.CrossRefGoogle Scholar
  23. 23.
    Lopez-Moya F, Lopez-Llorca L. Omics for investigating chitosan as an antifungal and gene modulator. J Fungi. 2016;2(1):11.CrossRefGoogle Scholar
  24. 24.
    Kobayashi Y, Komatsu T, Sumi M, Numajiri S, Miyamoto M, Kobayashi D, et al. In vitro permeation of several drugs through the human nail plate: relationship between physicochemical properties and nail permeability of drugs. Eur J Pharm Sci. 2004;21(4):471–7.CrossRefGoogle Scholar
  25. 25.
    Miron D, Cornelio R, Troleis J, Mariath J, Zimmer A, Mayorga P, et al. Influence of penetration enhancers and molecular weight in antifungals permeation through bovine hoof membranes and prediction of efficacy in human nails. Eur J Pharm Sci. 2014;51:20–5.CrossRefGoogle Scholar
  26. 26.
    Kobayashi Y, Miyamoto M, Sugibayashi K, Morimoto Y. Enhancing effect of N-acetyl-L-cysteine or 2-mercaptoethanol on the in vitro permeation of 5-fluorouracil or tolnaftate through the human nail plate. Chem Pharm Bull. 1998;46(11):1797–802.CrossRefGoogle Scholar
  27. 27.
    Donnelly R, McCarron P, Lightowler J, Woolfson A. Bioadhesive patch-based delivery of 5-aminolevulinic acid to the nail for photodynamic therapy of onychomycosis. J Control Release. 2005;103(2):381–92.CrossRefGoogle Scholar
  28. 28.
    British Pharmacopoeia 2014. Volume 5. London: The Stationery Office Appendix 1D;2013.Google Scholar
  29. 29.
    Moser M, Schmid R, Schindel R, Hildebrandt G. Patient-specific polymethylmethacrylate prostheses for secondary reconstruction of large calvarial defects: a retrospective feasibility study of a new intraoperative moulding device for cranioplasty. J Cranio-Maxillofac Surg. 2017;45(2):295–303.CrossRefGoogle Scholar
  30. 30.
    Stournaras A, Stavropoulos P, Salonitis K, Chryssolouris G. An investigation of quality in CO2 laser cutting of aluminum. CIRP J Manuf Sci Technol. 2009;2(1):61–9.CrossRefGoogle Scholar
  31. 31.
    Huang Y, Onyeri S, Siewe M, Moshfeghian A, Madihally S. In vitro characterization of chitosan–gelatin scaffolds for tissue engineering. Biomaterials. 2005;26(36):7616–27.CrossRefGoogle Scholar
  32. 32.
    Pezeshki-Modaress M, Zandi M, Mirzadeh H. Fabrication of gelatin/chitosan nanofibrous scaffold: process optimization and empirical modeling. Polym Int. 2014;64(4):571–80.CrossRefGoogle Scholar
  33. 33.
    Sionkowska A. Molecular interactions in collagen and chitosan blends. Biomaterials. 2004;25(5):795–801.CrossRefGoogle Scholar
  34. 34.
    Hosseini S, Rezaei M, Zandi M, Ghavi F. Preparation and functional properties of fish gelatin–chitosan blend edible films. Food Chem. 2013;136(3–4):1490–5.CrossRefGoogle Scholar
  35. 35.
    Shah B, Kakumanu V, Bansal A. Analytical techniques for quantification of amorphous/crystalline phases in pharmaceutical solids. J Pharm Sci. 2006;95(8):1641–65.CrossRefGoogle Scholar
  36. 36.
    Kuminek G, Rauber G, Riekes M, Campos C, Monti G, Bortoluzzi A, et al. Single crystal structure, solid state characterization and dissolution rate of terbinafine hydrochloride. J Pharm Biomed Anal. 2013;78(79):105–11.CrossRefGoogle Scholar
  37. 37.
    Cunha-Filho M, Alvarez-Lorenzo C, Martínez-Pacheco R, Landin M. Temperature-sensitive gels for Intratumoral delivery of β-lapachone: effect of cyclodextrins and ethanol. Sci World J. 2012;2012:1–8.CrossRefGoogle Scholar
  38. 38.
    Smithey D, Friesen D, Miller W, Babcock W. Solid compositions of low-solubility drugs and poloxamers. US Patent 2007/0141143 A1, 2007.Google Scholar
  39. 39.
    Rajendra VB, Baro A, Kumari A, Dhamecha DL, Lahoti SR, Shelke SD. Transungual drug delivery: an overview. J Appl Pharm Sci. 2012;2(1):203–9.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Esra’a Albarahmieh
    • 1
    Email author
  • Labiba AbuAmmouneh
    • 1
  • Zaina Kaddoura
    • 1
  • Farah AbuHantash
    • 1
  • Bashar A. Alkhalidi
    • 2
  • Alaaldeen Al-Halhouli
    • 3
  1. 1.Pharmaceutical Chemical Engineering Department, School of Applied Medical SciencesGerman Jordanian UniversityAmmanJordan
  2. 2.School of PharmacyUniversity of JordanAmmanJordan
  3. 3.NanoLab, School of Applied Technical SciencesGerman Jordanian UniversityAmmanJordan

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