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Rapidly separable microneedle patch for the sustained release of a contraceptive


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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Fig. 1: Design and fabrication of rapidly separable microneedle patches.
Fig. 2: Characterization of rapidly separable microneedle patches.
Fig. 3: Mechanical performance of rapidly separable microneedle patches.
Fig. 4: Application of rapidly separable microneedle patches to porcine skin ex vivo.
Fig. 5: Histological images of microneedles embedded in porcine skin ex vivo.
Fig. 6: Release of LNG from rapidly separable microneedle patches in vitro and in vivo in rats.
Fig. 7: Imaging of dye release from rapidly separable microneedle patches in vivo in female Sprague Dawley rats.

Data availability

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


  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).

    Article  Google Scholar 

  2. 2.

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

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    Article  Google Scholar 

  7. 7.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  9. 9.

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

    Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  13. 13.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  22. 22.

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

    CAS  Article  Google Scholar 

  23. 23.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  26. 26.

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

    CAS  Article  Google Scholar 

  27. 27.

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

    CAS  Article  Google Scholar 

  28. 28.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    Article  Google Scholar 

  31. 31.

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

    CAS  Article  Google Scholar 

  32. 32.

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

    Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  38. 38.

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

    CAS  Article  Google Scholar 

  39. 39.

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

    CAS  Article  Google Scholar 

  40. 40.

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

    Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  44. 44.

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

    CAS  Article  Google Scholar 

  45. 45.

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

    Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  47. 47.

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

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  51. 51.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  63. 63.

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

    CAS  Article  Google Scholar 

  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.

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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.

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Correspondence to Mark R. Prausnitz.

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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.

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Li, W., Terry, R.N., Tang, J. et al. Rapidly separable microneedle patch for the sustained release of a contraceptive. Nat Biomed Eng 3, 220–229 (2019).

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