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Rapidly separable microneedle patch for the sustained release of a contraceptive

Nature Biomedical Engineering (2019) | Download Citation


Women often have limited access to contraception, and barrier methods have low acceptance and a high failure rate, mostly due to incorrect use, which can result in unplanned pregnancies. Sustained-release formulations of contraceptive hormones are available, yet typically require their administration by trained personnel. Here, we report the design of a microneedle patch with rapidly separable biodegradable polylactic acid and polylactic-co-glycolic acid needles, and its application for the continuous release of levonorgestrel—a contraceptive hormone. Bubble structures between each microneedle and the patch backing allow the microneedles to efficiently penetrate skin under compression, and to snap off under shear within five seconds after patch administration. In rats, the microneedle patch was well tolerated, leaving little visible evidence of use, and maintained plasma concentrations of the hormone above the human therapeutic level for one month. Further development of the rapidly separable microneedle patch for self-administered, long-acting contraception could enable women to better control their fertility.

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The authors declare that all data supporting the results in this study are available within the paper and its Supplementary Information. Source data for the figures in this study are available from figshare with the identifier

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  1. 1.

    Sedgh, G., Singh, S. & Hussain, R. Intended and unintended pregnancies worldwide in 2012 and recent trends. Stud. Family Plan. 45, 301–314 (2014).

  2. 2.

    Sedgh, G. et al. Abortion incidence between 1990 and 2014: global, regional, and subregional levels and trends. Lancet 388, 258–267 (2016).

  3. 3.

    Rose, E. et al. The validity of teens’ and young adults’ self-reported condom use. Arch. Pediatr. Adolesc. Med. 163, 61–64 (2009).

  4. 4.

    Macaluso, M. et al. Mechanical failure of the latex condom in a cohort of women at high STD risk. Sex. Transm. Dis. 26, 450–458 (1999).

  5. 5.

    Galzote, R. M., Rafie, S., Teal, R. & Mody, S. K. Transdermal delivery of combined hormonal contraception: a review of the current literature. Int. J. Womens Health 9, 315–321 (2017).

  6. 6.

    Mansour, D., Inki, P. & Gemzell-Danielsson, K. Efficacy of contraceptive methods: a review of the literature. Eur. J. Contracept. Reprod. Health Care 15, S19–S31 (2010).

  7. 7.

    Petitti, D. B. et al. Stroke in users of low-dose oral contraceptives. New Engl. J. Med. 335, 8–15 (1996).

  8. 8.

    Halpern, V. et al. Towards the development of a longer-acting injectable contraceptive: past research and current trends. Contraception 92, 3–9 (2015).

  9. 9.

    Prescott, G. M. & Matthews, C. M. Long-acting reversible contraception: a review in special populations. Pharmacotherapy 34, 46–59 (2014).

  10. 10.

    Makadia, H. K. & Siegel, S. J. Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier. Polymers (Basel) 3, 1377–1397 (2011).

  11. 11.

    Tyler, B., Gullotti, D., Mangraviti, A., Utsuki, T. & Brem, H. Polylactic acid (PLA) controlled delivery carriers for biomedical applications. Adv. Drug Deliv. Rev. 107, 163–175 (2016).

  12. 12.

    Sun, Y. et al. Synchronic release of two hormonal contraceptives for about one month from the PLGA microspheres: in vitro and in vivo studies. J. Control. Release 129, 192–199 (2008).

  13. 13.

    Lee, B. K., Yun, Y. & Park, K. PLA micro- and nano-particles. Adv. Drug Deliv. Rev. 107, 176–191 (2016).

  14. 14.

    Wu, L. F., Janagam, D. R., Mandrell, T. D., Johnson, J. R. & Lowe, T. L. Long-acting injectable hormonal dosage forms for contraception. Pharm. Res. 32, 2180–2191 (2015).

  15. 15.

    Dicko, M. et al. Safety of immunization injections in Africa: not simply a problem of logistics. Bull. World Health Organ. 78, 163–169 (2000).

  16. 16.

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

  17. 17.

    Li, G. H., Badkar, A., Nema, S., Kolli, C. S. & Banga, A. K. In vitro transdermal delivery of therapeutic antibodies using maltose microneedles. Int. J. Pharm. 368, 109–115 (2009).

  18. 18.

    Yu, J. C. et al. Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery. Proc. Natl Acad. Sci. USA 112, 8260–8265 (2015).

  19. 19.

    Chen, M. C., Lin, Z. W. & Ling, M. H. Near-infrared light-activatable microneedle system for treating superficial tumors by combination of chemotherapy and photothermal therapy. ACS Nano 10, 93–101 (2016).

  20. 20.

    Ye, Y. Q. et al. Microneedles integrated with pancreatic cells and synthetic glucose-signal amplifiers for smart insulin delivery. Adv. Mater. 28, 3115–3121 (2016).

  21. 21.

    Yao, G. T. et al. Novel dissolving microneedles for enhanced transdermal delivery of levonorgestrel: in vitro and in vivo characterization. Int. J. Pharm. 534, 378–386 (2017).

  22. 22.

    Sullivan, S. P. et al. Dissolving polymer microneedle patches for influenza vaccination. Nat. Med. 16, 915–920 (2010).

  23. 23.

    DeMuth, P. C. et al. Vaccine delivery with microneedle skin patches in nonhuman primates. Nat. Biotech. 31, 1082–1085 (2013).

  24. 24.

    Chen, M. C., Huang, S. F., Lai, K. Y. & Ling, M. H. Fully embeddable chitosan microneedles as a sustained release depot for intradermal vaccination. Biomaterials 34, 3077–3086 (2013).

  25. 25.

    Chen, X. F. et al. Dry-coated microprojection array patches for targeted delivery of immunotherapeutics to the skin. J. Control. Release 139, 212–220 (2009).

  26. 26.

    DeMuth, P. C. et al. Polymer multilayer tattooing for enhanced DNA vaccination. Nat. Mater. 12, 367–376 (2013).

  27. 27.

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

  28. 28.

    Zhang, Y. Q. et al. Locally induced adipose tissue browning by microneedle patch for obesity treatment. ACS Nano 11, 9223–9230 (2017).

  29. 29.

    DeMuth, P. C., Garcia-Beltran, W. F., Ai-Ling, M. L., Hammond, P. T. & Irvine, D. J. Composite dissolving microneedles for coordinated control of antigen and adjuvant delivery kinetics in transcutaneous vaccination. Adv. Funct. Mater. 23, 161–172 (2013).

  30. 30.

    Gill, H. S., Denson, D. D., Burris, B. A. & Prausnitz, M. R. Effect of microneedle design on pain in human volunteers. Clin. J. Pain 24, 585–594 (2008).

  31. 31.

    Haq, M. I. et al. Clinical administration of microneedles: skin puncture, pain and sensation. Biomed. Microdevices 11, 35–47 (2009).

  32. 32.

    Norman, J. J. et al. Microneedle patches: usability and acceptability for self-vaccination against influenza. Vaccine 32, 1856–1862 (2014).

  33. 33.

    Rouphael, N. G. et al. The safety, immunogenicity, and acceptability of inactivated influenza vaccine delivered by microneedle patch (TIV-MNP 2015): a randomised, partly blinded, placebo-controlled, phase 1 trial. Lancet 390, 649–658 (2017).

  34. 34.

    Daddona, P. E., Matriano, J. A., Mandema, J. & Maa, Y. F. Parathyroid hormone (1-34)-coated microneedle patch system: clinical pharmacokinetics and pharmacodynamics for treatment of osteoporosis. Pharm. Res. 28, 159–165 (2011).

  35. 35.

    Hirobe, S. et al. Clinical study and stability assessment of a novel transcutaneous influenza vaccination using a dissolving microneedle patch. Biomaterials 57, 50–58 (2015).

  36. 36.

    Uppuluri, C. T. et al. Microneedle-assisted transdermal delivery of Zolmitriptan: effect of microneedle geometry, in vitro permeation experiments, scaling analyses and numerical simulations. Drug Dev. Ind. Pharm. 43, 1292–1303 (2017).

  37. 37.

    Polaneczky, M., Slap, G., Forke, C., Rappaport, A. & Sondheimer, S. The use of levonorgestrel implants (Norplant) for contraception in adolescent mothers. New Engl. J. Med. 331, 1201–1206 (1994).

  38. 38.

    Sivin, I. Risks and benefits, advantages and disadvantages of levonorgestrel-releasing contraceptive implants. Drug. Saf. 26, 303–335 (2003).

  39. 39.

    Prausnitz, M. R. Microneedles for transdermal drug delivery. Adv. Drug Deliv. Rev. 56, 581–587 (2004).

  40. 40.

    Bao, S. & Silverstein, B. Estimation of hand force in ergonomic job evaluations. Ergonomics 48, 288–301 (2005).

  41. 41.

    Wang, S. H. et al. Controlled release of levonorgestrel from biodegradable poly(d,l-lactide-co-glycolide) microspheres: in vitro and in vivo studies. Int. J. Pharm. 301, 217–225 (2005).

  42. 42.

    Zolnik, B. S. & Burgess, D. J. Evaluation of in vivo–in vitro release of dexamethasone from PLGA microspheres. J. Control. Release 127, 137–145 (2008).

  43. 43.

    Doty, A. C. et al. Mechanisms of in vivo release of triamcinolone acetonide from PLGA microspheres. J. Control. Release 256, 19–25 (2017).

  44. 44.

    Fotherby, K. Levonorgestrel—clinical pharmacokinetics. Clin. Pharmacokinet. 28, 203–215 (1995).

  45. 45.

    Kohn, J. E. DMPA self-administration can improve contraceptive access, continuation, and autonomy. Lancet Glob. Health 6, E481–E482 (2018).

  46. 46.

    Novikova, N., Weisberg, E., Stanczyk, F. Z., Croxatto, H. B. & Fraser, I. S. Effectiveness of levonorgestrel emergency contraception given before or after ovulation—a pilot study. Contraception 75, 112–118 (2007).

  47. 47.

    Anderson, J. M. & Shive, M. S. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv. Drug Deliv. Rev. 64, 72–82 (2012).

  48. 48.

    Higginbottom, G. M. A. et al. “I have to do what I believe”: Sudanese women’s beliefs and resistance to hegemonic practices at home and during experiences of maternity care in Canada. BMC Pregnancy Childb. 13, 51 (2013).

  49. 49.

    Wang, Q. L., Zhu, D. D., Liu, X. B., Chen, B. Z. & Guo, X. D. Microneedles with controlled bubble sizes and drug distributions for efficient transdermal drug delivery. Sci. Rep. 6, 38755 (2016).

  50. 50.

    Chu, L. Y., Choi, S. O. & Prausnitz, M. R. Fabrication of dissolving polymer microneedles for controlled drug encapsulation and delivery: bubble and pedestal microneedle designs. J. Pharm. Sci. 99, 4228–4238 (2010).

  51. 51.

    Chu, L. Y. & Prausnitz, M. R. Separable arrowhead microneedles. J. Control. Release 149, 242–249 (2011).

  52. 52.

    Zhu, D. D., Wang, Q. L., Liu, X. B. & Guo, X. D. Rapidly separating microneedles for transdermal drug delivery. Acta Biomater. 41, 312–319 (2016).

  53. 53.

    Zhu, D. D., Chen, B. Z., He, M. C. & Guo, X. D. Structural optimization of rapidly separating microneedles for efficient drug delivery. J. Ind. Eng. Chem. 51, 178–184 (2017).

  54. 54.

    Abrams, L. S., Skee, D. A., Natarajan, J., Wong, F. A. & Lasseter, K. C. Multiple-dose pharmacokinetics of a contraceptive patch in healthy women participants. Contraception 64, 287–294 (2001).

  55. 55.

    Sivin, I. et al. First week drug concentrations in women with levonorgestrel rod or Norplant (R) capsule implants. Contraception 56, 317–321 (1997).

  56. 56.

    Huang, X. & Brazel, C. S. On the importance and mechanisms of burst release in matrix-controlled drug delivery systems. J. Control. Release 73, 121–136 (2001).

  57. 57.

    Wang, J., Wang, B. A. & Schwendeman, S. P. Characterization of the initial burst release of a model peptide from poly(d,l-lactide-co-glycolide) microspheres. J. Control. Release 82, 289–307 (2002).

  58. 58.

    Avgoustakis, K. in Encyclopedia of Biomaterials and Biomedical Engineering 2259–2269 (Informa, New York, 2008).

  59. 59.

    Lupron Depot (Leuprolide Acetate for Depot Suspension) (AbbVie, 2016).

  60. 60.

    Larraneta, E., Lutton, R. E. M., Woolfson, A. D. & Donnelly, R. F. Microneedle arrays as transdermal and intradermal drug delivery systems: materials science, manufacture and commercial development. Mat. Sci. Eng. R 104, 1–32 (2016).

  61. 61.

    Overcashier, D. E., Patapoff, T. W. & Hsu, C. C. Lyophilization of protein formulations in vials: investigation of the relationship between resistance to vapor flow during primary drying and small-scale product collapse. J. Pharm. Sci. 88, 688–695 (1999).

  62. 62.

    Penning, T. M., Lee, S. H., Jin, Y., Gutierrez, A. & Blair, I. A. Liquid chromatography-mass spectrometry (LC-MS) of steroid hormone metabolites and its applications. J. Steroid Biochem. Mol. Biol. 121, 546–555 (2010).

  63. 63.

    Gabrielsson, J. & Weiner, D. Non-compartmental analysis. Methods Mol. Biol. 929, 377–389 (2012).

  64. 64.

    Gibaldi, M. & Perrier, D. Pharmacokinetics 2nd edn (M. Dekker, New York, 1982).

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We thank D. Owen, G. S. Kopf and J. Ayres of FHI 360 for valuable technical discussions and review of the manuscript, and D. Bondy and A. Troxler for administrative support. This publication is made possible by the generous support of the American people through the U.S. Agency for International Development (USAID) and was prepared under a subcontract funded by Family Health International under Cooperative Agreement No. AID-OAA-15-00045, funded by USAID. The content of this publication does not necessarily reflect the views, analysis or policies of FHI 360, USAID or the United States Government, nor does any mention of trade names, commercial products, or organizations imply endorsement by FHI 360, USAID or the United States Government.

Author information


  1. School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA

    • Wei Li
    • , Richard N. Terry
    •  & Mark R. Prausnitz
  2. Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA

    • Jie Tang
    • , Meihua R. Feng
    •  & Steven P. Schwendeman


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W.L., J.T., S.P.S. and M.R.P. designed the project. W.L. and M.R.P. wrote the manuscript, with contributions from R.N.T., J.T., M.R.F. and S.P.S. W.L., R.N.T. and J.T. performed the experiments. All authors analysed and interpreted the data.

Competing interests

M.R.P. is an inventor of patents licensed to companies developing microneedle-based products, a paid advisor to companies developing microneedle-based products, and a founder/shareholder of companies developing microneedle-based products (Micron Biomedical). This potential conflict of interest has been disclosed and is managed by Georgia Tech and Emory University.

Corresponding author

Correspondence to Mark R. Prausnitz.

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