AAPS PharmSciTech

, Volume 18, Issue 8, pp 2936–2948 | Cite as

Fabrication, Physicochemical Characterization, and Performance Evaluation of Biodegradable Polymeric Microneedle Patch System for Enhanced Transcutaneous Flux of High Molecular Weight Therapeutics

Research Article


A revolutionary paradigm shift is being observed currently, towards the use of therapeutic biologics for disease management. The present research was focused on designing an efficient dosage form for transdermal delivery of α-choriogonadotropin (high molecular weight biologic), through biodegradable polymeric microneedles. Polyvinylpyrrolidone-based biodegradable microneedle arrays loaded with high molecular weight polypeptide, α-choriogonadotropin, were fabricated for its systemic delivery via transdermal route. Varied process and formulation parameters were optimized for fabricating microneedle array, which in turn was expected to temporally rupture the stratum corneum layer of the skin, acting as a major barrier to drug delivery through transdermal route. The developed polymeric microneedles were optimized on the basis of quality attributes like mechanical strength, axial strength, insertion ratio, and insertion force analysis. The optimized polymeric microneedle arrays were characterized for in vitro drug release studies, ex vivo drug permeation studies, skin resealing studies, and in vivo pharmacokinetic studies. Results depicted that fabricated polymeric microneedle arrays with mechanical strength of above 5 N and good insertion ratio exhibited similar systemic bioavailability of α-choriogonadotropin in comparison to marketed subcutaneous injection formulation of α-choriogonadotropin. Thus, it was ultimately concluded that the designed drug delivery system can serve as an efficient tool for systemic delivery of therapeutic biologics, with an added benefit of overcoming the limitations of parenteral delivery, achieving better patient acceptability and compliance.


biodegradable polymers polymeric microneedles protein and peptide delivery therapeutic biologics α-choriogonadotropin 


Compliance with Ethical Standards

All the animal experiments were conducted in full compliance with local ethical and regulatory principles and local licensing regulations, as per the spirit of Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). The preclinical experiments were approved by IAEC of PERD Centre, Ahmedabad, approval no. PERD/IAEC/2014/019


  1. 1.
    Patrick C, Marc Van R, Etienne W, Daniel B. Therapeutic antibodies: success, limitations, and hopes for the future. Br J Pharmacol. 2009;157(2):220–33.CrossRefGoogle Scholar
  2. 2.
    Shah V, Kalia K. Therapeutic biologics: challenges and opportunities. In: Express pharma. 2015:http://www.expressbpd.com/pharma/pharma-life/therapeutic-biologicals-challenges-and-opportunities/173767.
  3. 3.
    Natasa S. Biologics: the role of delivery systems in improved therapy. Biologics. 2014;8:107–14.Google Scholar
  4. 4.
    Illum L. Nasal drug delivery-possibilities, problems, and solutions. J Control Release. 2003;87:187–98.CrossRefPubMedGoogle Scholar
  5. 5.
    Chinnareddy P, Chaitaniya K, Madhusudan RY. A review on bioadhesive buccal drug delivery systems: current status of formulation and evaluation methods. Daru. 2011;19(6):385–403.Google Scholar
  6. 6.
    Ita K. Transdermal drug delivery: progress and challenges. J Drug Deliv Sci Technol. 2014;24:245–50.CrossRefGoogle Scholar
  7. 7.
    Schoellhammer C, Blankschtein D, Langer R. Skin permeabilization for transdermal drug delivery: recent advances and future prospects. Expert Opin Drug Deliv. 2014;11:393–407.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Han T, Das D. Potential of combined ultrasound and microneedles for enhanced transdermal drug permeation: a review. Eur J Pharm Biopharm. 2015;89:312–28.CrossRefPubMedGoogle Scholar
  9. 9.
    Nir Y, Paz A, Sabo E, Potasman I. Fear of injections in young adults: prevalence and associations. AmJTrop Med Hyg. 2003;68(3):341–4.Google Scholar
  10. 10.
    Kermode M. Unsafe injections in low-income country health settings: need for injection safety promotion to prevent the spread of blood-borne viruses. Health Promot Int. 2004;19(1):95–103.CrossRefPubMedGoogle Scholar
  11. 11.
    Arora A, Prausnitz MR, Mitragotri S. Micro-scale devices for transdermal drug delivery. Int J Pharm. 2008;364(2):227–36.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Sahni K, Kassir M. Dermafrac™: an innovative new treatment for periorbital melanosis in a dark-skinned male patient. Journal of cutaneous and aesthetic. surgery. 2013;6(3):158–60.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Singh A, Yadav S. Microneedling: advances and widening horizons. Indian Dermatol. 2016;7(4):244–54.CrossRefGoogle Scholar
  14. 14.
    Donnelly RF, Singh TRR, Woolfson AD. Microneedle-based drug delivery systems: microfabrication, drug delivery, and safety. Drug Deliv. 2010;17(4):187–207.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Arora S, Gupta PB. Automated microneedling device—a new tool in dermatologist’s kit—a review. JPAD. 2012;22(4):354–7.Google Scholar
  16. 16.
    Kang S-M, Song J-M, Kim Y-C. Microneedle and mucosal delivery of influenza vaccines. Expert Rev Vaccines. 2012;11(5):547–60.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Mohammed YH, Yamada M, Lin LL, Grice JE, Roberts MS, Raphael AP. Microneedle enhanced delivery of cosmeceutically relevant peptides in human skin. PLoS One. 2014;9(7):e101956. doi: 10.1371/journal.pone.0101956.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Koutsonanos DG, Martin MP, Zarnitsyn VG, Sullivan SP, Compans RW, Prausnitz MR. Transdermal influenza immunization with vaccine-coated microneedle arrays. PLoS One. 2009;4(3):e4773. doi: 10.1371/journal.pone.0004773.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kim Y-C, Park J-H, Prausnitz MR. Microneedles for drug and vaccine delivery. Adv Drug Deliv Rev. 2012;64(14):1547–68.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Chen X, Fernando GJ, Crichton ML, Flaim C, Yukiko SR, Fairmaid EJ, et al. Improving the reach of vaccines to low-resource regions, with a needle-free vaccine delivery device and long-term thermostabilization. J Control Release. 2011;152(3):349–55.CrossRefPubMedGoogle Scholar
  21. 21.
    Garland MJ, Migalska K, Mahmood TMT, Singh TRR. Woolfson a D, Donnelly RF. Microneedle arrays as medical devices for enhanced transdermal drug delivery. Expert Rev Med Devices. 2011;8(4):459–82.CrossRefPubMedGoogle Scholar
  22. 22.
    Birchall JC, Clemo R, Anstey A, John DN. Microneedles in clinical practice—an exploratory study into the opinions of healthcare professionals and the public. Pharm Res. 2011;28(1):95–106.CrossRefPubMedGoogle Scholar
  23. 23.
    Shah UU, Roberts M, Gul MO, Tuleu C, Beresford MW. Needle-free and microneedle drug delivery in children: a case for disease-modifying antirheumatic drugs (DMARDs). Int J Pharm. 2011;416(1):1–11.CrossRefPubMedGoogle Scholar
  24. 24.
    Giudice EL, Campbell JD. Needle-free vaccine delivery. Adv Drug Deliv Rev. 2006;58(1):68–89.CrossRefPubMedGoogle Scholar
  25. 25.
    Brogden NK, Banks SL, Crofford LJ, Stinchcomb AL. Diclofenac enables unprecedented week-long microneedle-enhanced delivery of a skin impermeable medication in humans. Pharm Res. 2013;30(8):1947–55.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Dogra S, Yadav S, Sarangal R. Microneedling for acne scars in Asian skin type: an effective low cost treatment modality. J Cosmet Dermatol. 2014;13(3):180–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Weldon WC, Martin MP, Zarnitsyn V, Wang B, Koutsonanos D, Skountzou I, et al. Microneedle vaccination with stabilized recombinant influenza virus hemagglutinin induces improved protective immunity. Clin Vaccine Immunol. 2011;18(4):647–54.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Budamakuntla L, Loganathan E, Suresh DH, Shanmugam S, Suryanarayan S, Dongare A, et al. A randomized, open-label, comparative study of tranexamic acid microinjections and tranexamic acid with microneedling in patients with melasma. Journal of cutaneous and aesthetic surgery. 2013;6(3):139–43.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    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. 2010;391(1):7–12.CrossRefPubMedGoogle Scholar
  30. 30.
    Martin C, Allender CJ, Brain KR, Morrissey A, Birchall JC. Low temperature fabrication of biodegradable sugar glass microneedles for transdermal drug delivery applications. J Control Release. 2012;158(1):93–101.CrossRefPubMedGoogle Scholar
  31. 31.
    Kim Y-C, Quan F-S, Compans RW, Kang S-M, Prausnitz MR. Formulation of microneedles coated with influenza virus-like particle vaccine. AAPS PharmSciTech. 2010;11(3):1193–201.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Bal SM, Slütter B, Jiskoot W, Bouwstra JA. Small is beautiful: N-trimethyl chitosan–ovalbumin conjugates for microneedle-based transcutaneous immunization. Vaccine. 2011;29(23):4025–32.CrossRefPubMedGoogle Scholar
  33. 33.
    McCrudden MT, Alkilani AZ, McCrudden CM, McAlister E, McCarthy HO, Woolfson AD, et al. Design and physicochemical characterisation of novel dissolving polymeric microneedle arrays for transdermal delivery of high dose, low molecular weight drugs. J Control Release. 2014;180:71–80.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Ansaldi F, Durando P, Icardi G. Intradermal influenza vaccine and new devices: a promising chance for vaccine improvement. Expert Opin Biol Ther. 2011;11(3):415–27.CrossRefPubMedGoogle Scholar
  35. 35.
    Zaric M, Lyubomska O, Touzelet O, Poux C, Al-Zahrani S, Fay F, et al. Skin dendritic cell targeting via microneedle arrays laden with antigen-encapsulated poly-D, L-lactide-co-glycolide nanoparticles induces efficient antitumor and antiviral immune responses. ACS Nano. 2013;7(3):2042–55.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Chen X, Kask AS, Crichton ML, McNeilly C, Yukiko S, Dong L, et al. Improved DNA vaccination by skin-targeted delivery using dry-coated densely-packed micro projection arrays. J Control Release. 2010;148(3):327–33.CrossRefPubMedGoogle Scholar
  37. 37.
    Lee K, Lee CY, Jung H. Dissolving microneedles for transdermal drug administration prepared by stepwise controlled drawing of maltose. Biomaterials. 2011;32(11):3134–40.CrossRefPubMedGoogle Scholar
  38. 38.
    Donnelly RF, McCrudden MT, Alkilani AZ, Larrañeta E, McAlister E, Courtenay AJ, et al. Hydrogel-forming microneedles prepared from “super swelling” polymers combined with lyophilised wafers for transdermal drug delivery. PLoS One. 2014;9(10):e111547.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Zhang Y, Brown K, Siebenaler K, Determan A, Dohmeier D, Hansen K. Development of lidocaine-coated microneedle product for rapid, safe, and prolonged local analgesic action. Pharm Res. 2012;29(1):170–7.CrossRefPubMedGoogle Scholar
  40. 40.
    Milewski M, Pinninti RR, Stinchcomb AL. Naltrexone salt selection for enhanced transdermal permeation through microneedle-treated skin. J Pharm Sci. 2012;101(8):2777–86.CrossRefPubMedGoogle Scholar
  41. 41.
    Peters EE, Ameri M, Wang X, Maa Y-F, Daddona PE. Erythropoietin-coated ZP-microneedle transdermal system: preclinical formulation, stability, and delivery. Pharm Res. 2012;29(6):1618–26.CrossRefPubMedGoogle Scholar
  42. 42.
    Marin A, Andrianov AK. Carboxymethylcellulose–chitosan-coated microneedles with modulated hydration properties. J Appl Polym Sci. 2011;121(1):395–401.CrossRefGoogle Scholar
  43. 43.
    Andrianov AK, Marin A, DeCollibus DP. Microneedles with intrinsic immunoadjuvant properties: microfabrication, protein stability, and modulated release. Pharm Res. 2011;28(1):58–65.CrossRefPubMedGoogle Scholar
  44. 44.
    Choi H-J, Yoo D-G, Bondy BJ, Quan F-S, Compans RW, Kang S-M, et al. Stability of influenza vaccine coated onto microneedles. Biomaterials. 2012;33(14):3756–69.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Ghosh P, Pinninti RR, Hammell DC, Paudel KS, Stinchcomb AL. Development of a codrug approach for sustained drug delivery across the microneedle-treated skin. J Pharm Sci. 2013;102(5):1458–67.CrossRefPubMedGoogle Scholar
  46. 46.
    Kim M, Jung B, Park J-H. Hydrogel swelling as a trigger to release biodegradable polymer microneedles in skin. Biomaterials. 2012;33(2):668–78.CrossRefPubMedGoogle Scholar
  47. 47.
    Koutsonanos DG, del Pilar MM, Zarnitsyn VG, Jacob J, Prausnitz MR, Compans RW, et al. Serological memory and long-term protection to novel H1N1 influenza virus after skin vaccination. J Infect Dis. 2011;204(4):582–91.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Kong X, Zhou P, Wu C. Numerical simulation of microneedles’ insertion into skin. Comput Methods Biomech Biomed Engin. 2011;14(9):827–35.CrossRefPubMedGoogle Scholar
  49. 49.
    Groves RB, Coulman S, Birchall JC, Evans SL. Quantifying the mechanical properties of human skin to optimize future microneedle device design. Comput Methods Biomech Biomed Engin. 2012;15(1):73–82.CrossRefPubMedGoogle Scholar
  50. 50.
    Noh Y-W, Kim T-H, Baek J-S, Park H-H, Lee SS, Han M, et al. In vitro characterization of the invasiveness of polymer microneedle against the skin. Int J Pharm. 2010;397(1):201–5.CrossRefPubMedGoogle Scholar
  51. 51.
    Demir YK, Akan Z, Kerimoglu O. Characterization of polymeric microneedle arrays for transdermal drug delivery. PLoS One. 2013;8(10):e77289.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Kumar A, Li X, Sandoval MA, Rodriguez BL, Sloat BR, Cui Z. Permeation of antigen protein-conjugated nanoparticles and live bacteria through microneedle-treated mouse skin. Int J Nanomedicine. 2011;6:1253–64.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Brogden NK, Ghosh P, Hardi L, Crofford LJ, Stinchcomb AL. Development of in vivo impedance spectroscopy techniques for measurement of micropore formation following microneedle insertion. J Pharm Sci. 2013;102(6):1948–56.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Crichton ML, Donose BC, Chen X, Raphael AP, Huang H, Kendall MA. The viscoelastic, hyperelastic and scale dependent behavior of freshly excised individual skin layers. Biomaterials. 2011;32(20):4670–81.CrossRefPubMedGoogle Scholar
  55. 55.
    Kalluri H, Kolli CS, Banga AK. Characterization of microchannels created by metal microneedles: formation and closure. AAPS J. 2011;13(3):473–81.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Gupta J, Gill HS, Andrews SN, Prausnitz MR. Kinetics of skin resealing after insertion of microneedles in human subjects. J Control Release. 2011;154(2):148–55.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Seo KY, Kim DH, Lee SE, Yoon MS, Lee HJ. Skin rejuvenation by microneedle fractional radiofrequency and a human stem cell conditioned medium in Asian skin: a randomized controlled investigator blinded split-face study. J Cosmet Laser Ther. 2013;15(1):25–33.CrossRefPubMedGoogle Scholar
  58. 58.
    Fukushima K, Yamazaki T, Hasegawa R, Ito Y, Sugioka N, Takada K. Pharmacokinetic and pharmacodynamic evaluation of insulin dissolving microneedles in dogs. Diabetes Technol Ther. 2010;12(6):465–74.CrossRefPubMedGoogle Scholar
  59. 59.
    Ito Y, Murano H, Hamasaki N, Fukushima K, Takada K. Incidence of low bioavailability of leuprolide acetate after percutaneous administration to rats by dissolving microneedles. Int J Pharm. 2011;407(1):126–31.CrossRefPubMedGoogle Scholar
  60. 60.
    Daddona PE, Matriano JA, Mandema J, Maa Y-F. Parathyroid hormone (1-34)-coated microneedle patch system: clinical pharmacokinetics and pharmacodynamics for the treatment of osteoporosis. Pharm Res. 2011;28(1):159–65.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  1. 1.Drug Discovery Laboratory, Department of PharmaceuticsNational Institute Of Pharmaceutical Education and Research - Ahmedabad (NIPER-A)PalajIndia

Personalised recommendations