Long-acting reversible contraception by effervescent microneedle patch

An effervescent microneedle patch has been designed for rapid separation of drug-loaded microneedles and long-term contraception. To increase access to long-acting contraception, we developed a reversible contraceptive microneedle patch that is simple-to-administer, slowly releases contraceptive hormone (levonorgestrel) for >1 month, and generates no biohazardous sharps waste. After manually pressing the patch to skin for 1 min, microneedles rapidly separate from the patch within the skin due to effervescence triggered by contact with skin’s interstitial fluid, as demonstrated in rats and human participants. Long-acting contraception is achieved by formulating microneedles with a biodegradable polymer [poly(lactic-co-glycolic) acid] that slowly releases levonorgestrel for ~1 month in vitro. In rats, the patch maintained levonorgestrel concentration above the human contraceptive threshold level for >1 month, and a placebo microneedle patch was well-tolerated in human participants. Women of reproductive age in three continents demonstrated interest in and preference for long-acting contraception by microneedle patch. These studies indicate that an effervescent microneedle patch could facilitate greater access to long-acting contraception.

[1]  J. Matriano,et al.  Parathyroid Hormone (1-34)-Coated Microneedle Patch System: Clinical Pharmacokinetics and Pharmacodynamics for Treatment of Osteoporosis , 2010, Pharmaceutical Research.

[2]  Jung-Hwan Park,et al.  Dissolving microneedles for transdermal drug delivery. , 2008, Biomaterials.

[3]  E. Espey,et al.  Long-Acting Reversible Contraceptives: Intrauterine Devices and the Contraceptive Implant , 2011, Obstetrics and gynecology.

[4]  Jung-Hwan Park,et al.  Human studies with microneedles for evaluation of their efficacy and safety , 2018, Expert opinion on drug delivery.

[5]  Ichiro Katayama,et al.  Clinical study and stability assessment of a novel transcutaneous influenza vaccination using a dissolving microneedle patch. , 2015, Biomaterials.

[6]  Mark G. Allen,et al.  Polymer Microneedles for Controlled-Release Drug Delivery , 2006, Pharmaceutical Research.

[7]  S. Zeng,et al.  Controlled release of levonorgestrel from biodegradable poly(D,L-lactide-co-glycolide) microspheres: in vitro and in vivo studies. , 2005, International journal of pharmaceutics.

[8]  M. C. Lindberg,et al.  Effect of dose on the pharmacokinetics of levonorgestrel in the rat during the rapid elimination phase following subcutaneous administration. , 1984, Contraception.

[9]  Mark R. Prausnitz,et al.  Rapidly separable microneedle patch for the sustained release of a contraceptive , 2019, Nature Biomedical Engineering.

[10]  Zhen Gu,et al.  Polymeric microneedles for transdermal protein delivery☆ , 2018, Advanced drug delivery reviews.

[11]  Ryan F. Donnelly,et al.  Successful application of large microneedle patches by human volunteers , 2017, International journal of pharmaceutics.

[12]  A. Kaunitz.  Long-acting injectable contraception with depot medroxyprogesterone acetate. , 1994, American journal of obstetrics and gynecology.

[13]  V. Newton,et al.  Young women’s experiences of side-effects from contraceptive implants: a challenge to bodily control , 2013, Reproductive health matters.

[14]  Christine L. Godwin,et al.  User preferences for a contraceptive microarray patch in India and Nigeria: Qualitative research on what women want , 2019, PloS one.

[15]  Karmen Cheung,et al.  Microneedles for drug delivery: trends and progress , 2016, Drug delivery.

[16]  Susheela Singh,et al.  Intended and unintended pregnancies worldwide in 2012 and recent trends. , 2014, Studies in family planning.

[17]  J. Hardin,et al.  The validity of teens' and young adults' self-reported condom use. , 2009, Archives of pediatrics & adolescent medicine.

[18]  C. Tuleu,et al.  Patient-Centered Pharmaceutical Design to Improve Acceptability of Medicines: Similarities and Differences in Paediatric and Geriatric Populations , 2014, Drugs.

[19]  K. Park,et al.  Park's Textbook of Preventive and Social Medicine , 2015 .

[20]  Zhen Gu,et al.  Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery , 2015, Proceedings of the National Academy of Sciences.

[21]  Z. Hel,et al.  Hormonal Contraception and HIV-1 Acquisition: Biological Mechanisms , 2018, Endocrine reviews.

[22]  L. Finer,et al.  Declines in Unintended Pregnancy in the United States, 2008–2011 , 2016 .

[23]  Dan Dan Zhu,et al.  Insulin delivery systems combined with microneedle technology. , 2018, Advanced drug delivery reviews.

[24]  Zhen Gu,et al.  Locally Induced Adipose Tissue Browning by Microneedle Patch for Obesity Treatment. , 2017, ACS nano.

[25]  Hirenkumar K. Makadia,et al.  Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier. , 2011, Polymers.

[26]  Shih-Fang Huang,et al.  Fully embeddable chitosan microneedles as a sustained release depot for intradermal vaccination. , 2013, Biomaterials.

[27]  Dan Dan Zhu,et al.  Rapidly separating microneedles for transdermal drug delivery. , 2016, Acta biomaterialia.

[28]  Ryan F. Donnelly,et al.  Microneedle arrays as transdermal and intradermal drug delivery systems: Materials science, manufacture and commercial development , 2016 .

[29]  Johan Gabrielsson,et al.  Non-compartmental analysis. , 2012, Methods in molecular biology.

[30]  Chenjie Xu,et al.  Recent advances in the design of polymeric microneedles for transdermal drug delivery and biosensing. , 2017, Lab on a chip.

[31]  Qiang Zhang,et al.  Synchronic release of two hormonal contraceptives for about one month from the PLGA microspheres: in vitro and in vivo studies. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[32]  Xin Pan,et al.  Novel dissolving microneedles for enhanced transdermal delivery of levonorgestrel: In vitro and in vivo characterization. , 2017, International journal of pharmaceutics.

[33]  E. Hook,et al.  Mechanical failure of the latex condom in a cohort of women at high STD risk. , 1999, Sexually transmitted diseases.

[34]  G. Molloy,et al.  Adherence to the oral contraceptive pill: a cross-sectional survey of modifiable behavioural determinants , 2012, BMC Public Health.

[35]  Mark R Prausnitz,et al.  Tolerability, usability and acceptability of dissolving microneedle patch administration in human subjects. , 2017, Biomaterials.

[36]  C Revillard,et al.  [Clinical pharmacokinetics]. , 1976, Schweizerische medizinische Wochenschrift.

[37]  K. Fotherby.  Levonorgestrel. Clinical pharmacokinetics. , 1995, Clinical pharmacokinetics.

[38]  W. Cates,et al.  Family planning and the post-2015 development agenda. , 2014, Bulletin of the World Health Organization.

[39]  Mark R Prausnitz,et al.  Separable arrowhead microneedles. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[40]  Mark R Prausnitz,et al.  Engineering Microneedle Patches for Vaccination and Drug Delivery to Skin. , 2017, Annual review of chemical and biomolecular engineering.

[41]  Paula T Hammond,et al.  Composite Dissolving Microneedles for Coordinated Control of Antigen and Adjuvant Delivery Kinetics in Transcutaneous Vaccination , 2012, Advanced functional materials.

[42]  Mark R Prausnitz,et al.  Insertion of microneedles into skin: measurement and prediction of insertion force and needle fracture force. , 2004, Journal of biomechanics.

[43]  L. Finer,et al.  Declines in Unintended Pregnancy in the United States, 2008-2011. , 2016, The New England journal of medicine.

[44]  Tianwei Yu,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 , 2017, The Lancet.

[45]  Mei-Chin Chen,et al.  Near-Infrared Light-Activatable Microneedle System for Treating Superficial Tumors by Combination of Chemotherapy and Photothermal Therapy. , 2016, ACS nano.

[46]  I. Frazer,et al.  Safety, tolerability, acceptability and immunogenicity of an influenza vaccine delivered to human skin by a novel high-density microprojection array patch (Nanopatch™). , 2018, Vaccine.