Skip to main content

Advertisement

SpringerLink
Log in

Innovative freeze-drying technique in the fabrication of dissolving microneedle patch: Enhancing transdermal drug delivery efficiency

  • Original Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

Microneedle patch (MNP) has become a hot research topic in the field of transdermal drug delivery due to its ability to overcome the stratum corneum barrier. Among the various types of microneedles, dissolving microneedles represent one of the most promising transdermal delivery methods. However, the most used method for preparing dissolving microneedles, namely microfabrication, suffers from issues such as long drying time, susceptibility to humidity, and large batch-to-batch variability, which limit the development of dissolving microneedles. In this study, we report for the first time a method for preparing dissolving microneedles using freeze-drying technology. We screened substrates suitable for freeze-dried microneedle patch (FD-MNP) and used coating technology to enhance the mechanical strength of FD-MNP, allowing them to meet the requirements for skin penetration. We successfully prepared FD-MNP using hyaluronic acid as the substrate and insulin as the model drug. Scanning electron microscopy revealed that the microneedles had a porous structure. After coating, the mechanical strength of the microneedles was 0.61 N/Needle, and skin penetration rate was 97%, with a penetration depth of 215 μm. The tips of the FD-MNP dissolved completely within approximately 60 s after skin penetration, which is much faster than conventional MNP (180 s). In vitro transdermal experiments showed that the FD-MNP shortened the lag time for transdermal delivery of rhodamine 123 and insulin compared to conventional MNP, indicating a faster transdermal delivery rate. Pharmacological experiments showed that the FD-MNP lowered mouse blood glucose levels more effectively than conventional MNP, with a relative pharmacological availability of 96.59 ± 2.84%, higher than that of conventional MNP (84.34 ± 3.87%), P = 0.0095. After storage under 40℃ for two months, the insulin content within the FD-MNP remained high at 95.27 ± 4.46%, which was much higher than that of conventional MNP (58.73 ± 3.71%), P < 0.0001. In conclusion, freeze-drying technology is a highly valuable method for preparing dissolving microneedles with potential applications in transdermal drug delivery.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

Data availability

All authors agree that any materials and data that are reasonably requested by others will be made available for noncommercial purposes.  The datasets generated during during the current study are available from the corresponding author on reasonable request.

References

  1. Dharadhar S, Majumdar A, Dhoble S, Patravale V. Microneedles for transdermal drug delivery: a systematic review. Drug Dev Ind Pharm. 2019;45:188–201. https://doi.org/10.1080/03639045.2018.1539497.

    Article  CAS  PubMed  Google Scholar 

  2. Morales JO, Fathe KR, Brunaugh A, Ferrati S, Li S, Montenegro-Nicolini M, Mousavikhamene Z, McConville JT, Prausnitz MR, Smyth HDC. Challenges and future prospects for the delivery of Biologics: oral mucosal, pulmonary, and Transdermal routes. AAPS J. 2017;19:652–68. https://doi.org/10.1208/s12248-017-0054-z.

    Article  CAS  PubMed  Google Scholar 

  3. Gill HS, Denson DD, Burris BA, Prausnitz MR. Effect of microneedle design on pain in human volunteers. Clin J Pain. 2008;24:585–94. https://doi.org/10.1097/AJP.0b013e31816778f9.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sullivan SP, Koutsonanos DG, Martin MdelP, Lee JW, Zarnitsyn V, Choi S-O, Murthy N, Compans RW, Skountzou I, Prausnitz MR. Dissolving polymer microneedle patches for influenza vaccination. Nat Med. 2010;16:915–20. https://doi.org/10.1038/nm.2182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Leone M, Priester MI, Romeijn S, Nejadnik MR, Mönkäre J, O’Mahony C, Jiskoot W, Kersten G, Bouwstra JA. Hyaluronan-based dissolving microneedles with high antigen content for intradermal vaccination: Formulation, physicochemical characterization and immunogenicity assessment. Eur J Pharm Biopharm. 2019;134:49–59. https://doi.org/10.1016/j.ejpb.2018.11.013.

    Article  CAS  PubMed  Google Scholar 

  6. Kim JD, Kim M, Yang H, Lee K, Jung H. Droplet-born air blowing: novel dissolving microneedle fabrication. J Controlled Release. 2013;170:430–6. https://doi.org/10.1016/j.jconrel.2013.05.026.

    Article  CAS  Google Scholar 

  7. Lee C, Kim H, Kim S, Lahiji SF, Ha N-Y, Yang H, Kang G, Nguyen HYT, Kim Y, Choi M-S, Cho N-H, Jung H. Comparative study of two droplet-based dissolving Microneedle fabrication methods for skin vaccination. Adv Healthc Mater. 2018;7:1701381. https://doi.org/10.1002/adhm.201701381.

    Article  CAS  Google Scholar 

  8. Lee K, Lee HC, Lee D-S, Jung H. Drawing lithography: three-Dimensional fabrication of an Ultrahigh-aspect-ratio Microneedle. Adv Mater. 2010;22:483–6. https://doi.org/10.1002/adma.200902418.

    Article  CAS  PubMed  Google Scholar 

  9. Xiang Z, Wang H, Murugappan SK, Yen S-C, Pastorin G, Lee C. Dense vertical SU-8 microneedles drawn from a heated mold with precisely controlled volume. J Micromech Microeng. 2015;25:025013. https://doi.org/10.1088/0960-1317/25/2/025013.

    Article  CAS  Google Scholar 

  10. Yang H, Kim S, Kang G, Lahiji SF, Jang M, Kim YM, Kim J-M, Cho S-N, Jung H. Centrifugal lithography: self-shaping of Polymer microstructures Encapsulating Biopharmaceutics by Centrifuging Polymer drops. Adv Healthc Mater. 2017;6:1700326. https://doi.org/10.1002/adhm.201700326.

    Article  CAS  Google Scholar 

  11. Han M, Kim DK, Kang SH, Yoon H-R, Kim B-Y, Lee SS, Kim KD, Lee HG. Improvement in antigen-delivery using fabrication of a grooves-embedded microneedle array. Sens Actuators B. 2009;137:274–80. https://doi.org/10.1016/j.snb.2008.11.017.

    Article  CAS  Google Scholar 

  12. Sammoura F, Kang J, Heo Y-M, Jung T, Lin L. Polymeric microneedle fabrication using a microinjection molding technique. Microsyst Technol. 2007;13:517–22. https://doi.org/10.1007/s00542-006-0204-1.

    Article  CAS  Google Scholar 

  13. Su Y, Mainardi VL, Wang H, McCarthy A, Zhang YS, Chen S, John JV, Wong SL, Hollins RR, Wang G, Xie J. Dissolvable microneedles coupled with Nanofiber Dressings Eradicate Biofilms via effectively delivering a database-designed antimicrobial peptide. ACS Nano. 2020;14:11775–86. https://doi.org/10.1021/acsnano.0c04527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yu J, Wang J, Zhang Y, Chen G, Mao W, Ye Y, Kahkoska AR, Buse JB, Langer R, Gu Z. Glucose-responsive insulin patch for the regulation of blood glucose in mice and minipigs. Nat Biomedical Eng. 2020;4:499–506. https://doi.org/10.1038/s41551-019-0508-y.

    Article  CAS  Google Scholar 

  15. Moore LE, Vucen S, Moore AC. Trends in drug- and vaccine-based dissolvable microneedle materials and methods of fabrication. Eur J Pharm Biopharm. 2022;173:54–72. https://doi.org/10.1016/j.ejpb.2022.02.013.

    Article  CAS  PubMed  Google Scholar 

  16. Li W, Terry RN, Tang J, Feng MR, Schwendeman SP, Prausnitz MR. Rapidly separable microneedle patch for the sustained release of a contraceptive. Nat Biomedical Eng. 2019;3:220–9. https://doi.org/10.1038/s41551-018-0337-4.

    Article  CAS  Google Scholar 

  17. Ling M-H, Chen M-C. Dissolving polymer microneedle patches for rapid and efficient transdermal delivery of insulin to diabetic rats. Acta Biomater. 2013;9:8952–61. https://doi.org/10.1016/j.actbio.2013.06.029.

    Article  CAS  PubMed  Google Scholar 

  18. Wang Q, Yao G, Dong P, Gong Z, Li G, Zhang K, Wu C. Investigation on fabrication process of dissolving microneedle arrays to improve effective needle drug distribution. Eur J Pharm Sci. 2015;66:148–56. https://doi.org/10.1016/j.ejps.2014.09.011.

    Article  CAS  PubMed  Google Scholar 

  19. Zeng Z, Jiang G, Liu T, Song G, Sun Y, Zhang X, Jing Y, Feng M, Shi Y. Fabrication of gelatin methacryloyl hydrogel microneedles for transdermal delivery of metformin in diabetic rats. Bio-Design and Manufacturing. 2021;4:902–11. https://doi.org/10.1007/s42242-021-00140-9.

    Article  CAS  Google Scholar 

  20. Chen X, Yu H, Wang L, Shen D, Li C, Zhou W. Cross-linking-density-changeable Microneedle Patch prepared from a glucose-responsive hydrogel for insulin delivery. ACS Biomater Sci Eng. 2021;7:4870–82. https://doi.org/10.1021/acsbiomaterials.1c01073.

    Article  CAS  PubMed  Google Scholar 

  21. Chang H, Chew SWT, Zheng M, Lio DCS, Wiraja C, Mei Y, Ning X, Cui M, Than A, Shi P, Wang D, Pu K, Chen P, Liu H, Xu C. Cryomicroneedles for transdermal cell delivery. Nat Biomedical Eng. 2021;5:1008–18. https://doi.org/10.1038/s41551-021-00720-1.

    Article  CAS  Google Scholar 

  22. Yu J, Kuwentrai C, Gong H-R, Li R, Zhang B-z, Lin X, Wang X, Huang J-D, Xu C. Intradermal delivery of mRNA using cryomicroneedles. Acta Biomater. 2022;148:133–41. https://doi.org/10.1016/j.actbio.2022.06.015.

    Article  CAS  PubMed  Google Scholar 

  23. Ye R, Yang J, Li Y, Zheng Y, Yang J, Li Y, Liu B, Jiang L. Fabrication of tip-hollow and tip-dissolvable microneedle arrays for Transdermal Drug Delivery. ACS Biomater Sci Eng. 2020;6:2487–94. https://doi.org/10.1021/acsbiomaterials.0c00120.

    Article  CAS  PubMed  Google Scholar 

  24. Rezvankhah A, Emam-Djomeh Z, Askari G. Encapsulation and delivery of bioactive compounds using spray and freeze-drying techniques: a review. Drying Technol. 2020;38:235–58. https://doi.org/10.1080/07373937.2019.1653906.

    Article  CAS  Google Scholar 

  25. Siow CRS, Wan Sia Heng P, Chan LW. Application of freeze-drying in the development of oral drug delivery systems. Expert Opin Drug Deliv. 2016;13:1595–608. https://doi.org/10.1080/17425247.2016.1198767.

    Article  CAS  PubMed  Google Scholar 

  26. Chu LY, Prausnitz MR. Separable arrowhead microneedles. J Controlled Release. 2011;149:242–9. https://doi.org/10.1016/jjconrel201010033.

    Article  CAS  Google Scholar 

  27. Sintov AC, Botner S. Transdermal drug delivery using microemulsion and aqueous systems: influence of skin storage conditions on the in vitro permeability of diclofenac from aqueous vehicle systems. Int J Pharm. 2006;311:55–62. https://doi.org/10.1016/j.ijpharm.2005.12.019.

    Article  CAS  PubMed  Google Scholar 

  28. Peng K, Vora LK, Tekko IA, Permana AD, Domínguez-Robles J, Ramadon D, Chambers P, McCarthy HO, Larrañeta E, Donnelly RF. Dissolving microneedle patches loaded with amphotericin B microparticles for localised and sustained intradermal delivery: potential for enhanced treatment of cutaneous fungal infections. J Controlled Release. 2021;339:361–80. https://doi.org/10.1016/j.jconrel.2021.10.001.

    Article  CAS  Google Scholar 

  29. Indermun S, Luttge R, Choonara YE, Kumar P, du Toit LC, Modi G, Pillay V. Current advances in the fabrication of microneedles for transdermal delivery. J Controlled Release. 2014;185:130–8. https://doi.org/10.1016/j.jconrel.2014.04.052.

    Article  CAS  Google Scholar 

  30. He X, Sun J, Zhuang J, Xu H, Liu Y, Wu D. Microneedle System for Transdermal Drug and Vaccine Delivery: Devices, Safety, and prospects. Dose-Response. 2019;17:1559325819878585. https://doi.org/10.1177/1559325819878585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Habib YS, Augsburger LL, Shangraw RF. Production of inert cushioning beads: effect of excipients on the physicomechanical properties of freeze-dried beads containing microcrystalline cellulose produced by extrusion–spheronization. Int J Pharm. 2002;233:67–83. https://doi.org/10.1016/S0378-5173(01)00924-3.

    Article  CAS  PubMed  Google Scholar 

  32. Assegehegn G, Brito-de la E, Fuente JM, Franco C, Gallegos. The importance of understanding the freezing step and its impact on freeze-drying process performance. J Pharm Sci. 2019;108:1378–95. https://doi.org/10.1016/jxphs201811039.

    Article  CAS  PubMed  Google Scholar 

  33. Searles JA, Carpenter JF, Randolph TW. The ice nucleation temperature determines the primary drying rate of lyophilization for samples frozen on a temperature-controlled shelf. J Pharm Sci. 2001;90:860–71. https://doi.org/10.1002/jps.1039.

    Article  CAS  PubMed  Google Scholar 

  34. Knopp MM, Löbmann K, Elder DP, Rades T, Holm R. Recent advances and potential applications of modulated differential scanning calorimetry (mDSC) in drug development. Eur J Pharm Sci. 2016;87:164–73. https://doi.org/10.1016/j.ejps.2015.12.024.

    Article  CAS  PubMed  Google Scholar 

  35. Park J-H, Allen MG, Prausnitz MR. Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery. J Controlled Release. 2005;104:51–66. https://doi.org/10.1016/j.jconrel.2005.02.002.

    Article  CAS  Google Scholar 

  36. Zhu J, Tang X, Jia Y, Ho C-T, Huang Q. Applications and delivery mechanisms of hyaluronic acid used for topical/transdermal delivery – a review. Int J Pharm. 2020;578:119127. https://doi.org/10.1016/j.ijpharm.2020.119127.

    Article  CAS  PubMed  Google Scholar 

  37. Zhu Q, Zarnitsyn VG, Ye L, Wen Z, Gao Y, Pan L, Skountzou I, Gill HS, Prausnitz MR, Yang C, Compans RW. Immunization by vaccine-coated microneedle arrays protects against lethal influenza virus challenge. Proc Natl Acad Sci. 2009;106:7968–73. https://doi.org/10.1073/pnas.0812652106.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  38. Kommareddy S, Baudner BC, Bonificio A, Gallorini S, Palladino G, Determan AS, Dohmeier DM, Kroells KD, Sternjohn JR, Singh M, Dormitzer PR, Hansen KJ, O’Hagan DT. Influenza subunit vaccine coated microneedle patches elicit comparable immune responses to intramuscular injection in guinea pigs. Vaccine. 31. 2013;3435–41. https://doi.org/10.1016/j.vaccine.2013.01.050.

    Article  CAS  PubMed  Google Scholar 

  39. Chen X, Kask AS, Crichton ML, McNeilly C, Yukiko S, Dong L, Marshak JO, Jarrahian C, Fernando GJP, Chen D, Koelle DM, Kendall MAF. Improved DNA vaccination by skin-targeted delivery using dry-coated densely-packed microprojection arrays. J Controlled Release. 2010;148:327–33. https://doi.org/10.1016/j.jconrel.2010.09.001.

    Article  CAS  Google Scholar 

  40. Ma Y, Gill HS. Coating solid dispersions on Microneedles via a molten dip-coating method: development and in vitro evaluation for Transdermal Delivery of a Water‐Insoluble Drug. J Pharm Sci. 2014;103:3621–30. https://doi.org/10.1002/jps.24159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pikal MJ, Rigsbee DR. The Stability of insulin in crystalline and amorphous solids: Observation of Greater Stability for the amorphous form. Pharm Res. 1997;14:1379–87. https://doi.org/10.1023/A:1012164520429.

    Article  CAS  PubMed  Google Scholar 

  42. 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;12:465–74. https://doi.org/10.1089/dia.2009.0176.

    Article  CAS  PubMed  Google Scholar 

  43. Chen M-C, Ling M-H, Kusuma SJ. Poly-γ-glutamic acid microneedles with a supporting structure design as a potential tool for transdermal delivery of insulin. Acta Biomater. 2015;24:106–16. https://doi.org/10.1016/jactbio201506021.

    Article  CAS  PubMed  Google Scholar 

  44. Men Z, Su T, Tang Z, Liang J, Shen T. Tacrolimus nanocrystals microneedle patch for plaque psoriasis. Int J Pharm. 2022;627:122207. https://doi.org/10.1016/j.ijpharm.2022.122207.

    Article  CAS  PubMed  Google Scholar 

  45. Zhu M, Liu Y, Jiang F, Cao J, Kundu SC, Lu S. Combined Silk Fibroin Microneedles for insulin delivery. ACS Biomater Sci Eng. 2020;6:3422–9. https://doi.org/10.1021/acsbiomaterials.0c00273.

    Article  CAS  PubMed  Google Scholar 

  46. Zhang Y, Jiang G, Yu W, Liu D, Xu B. Microneedles fabricated from alginate and maltose for transdermal delivery of insulin on diabetic rats. Mater Sci Engineering: C. 2018;85:18–26. https://doi.org/10.1016/jmsec201712006.

    Article  CAS  Google Scholar 

  47. Shi S, Wang Y, Mei R, Zhao X, Liu X, Chen L. Revealing drug release and diffusion behavior in skin interstitial fluid by surface-enhanced Raman scattering microneedles. J Mater Chem B. 2023;11:3097–105. https://doi.org/10.1039/D2TB02600G.

    Article  CAS  PubMed  Google Scholar 

  48. ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, Collins BS, Hilliard ME, Isaacs D, Johnson EL, Kahan S, Khunti K, Leon J, Lyons SK, Perry ML, Prahalad P, Pratley RE, Seley JJ, Stanton RC, Gabbay RA. A. on behalf of the American diabetes, 9. Pharmacologic approaches to Glycemic Treatment: standards of Care in Diabetes—2023. Diabetes Care. 2022;46:140. https://doi.org/10.2337/dc23-S009.

    Article  Google Scholar 

Download references

Acknowledgements

We acknowledge support from the Key Laboratory of Smart Drug Delivery, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, China.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author information

Author notes

  1. Tong Su and Zequn Tang these authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, People’s Republic of China

    Tong Su, Zequn Tang, Jiayi Hu, Yuyu Zhu & Teng Shen

  2. Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai, 201203, People’s Republic of China

    Teng Shen

Authors
  1. Tong Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zequn Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiayi Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuyu Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Teng Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Tong Su: Formal analysis, Methodology, Investigation, Visualization, Writing. Zequn Tang: Formal analysis, Data curation, Methodology, Investigation. Jiayi Hu: Validation. Yuyu Zhu: Validation. Teng Shen: Conceptualization, Writing- review & editing, Supervision.

Corresponding author

Correspondence to Teng Shen.

Ethics declarations

Ethics approval

The animal experiments throughout the study were evaluated and approved by the Experimental Animal Ethics Committee of the School of Pharmacy, Fudan University.

Competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 251 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Su, T., Tang, Z., Hu, J. et al. Innovative freeze-drying technique in the fabrication of dissolving microneedle patch: Enhancing transdermal drug delivery efficiency. Drug Deliv. and Transl. Res. (2024). https://doi.org/10.1007/s13346-024-01531-y

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s13346-024-01531-y

Keywords

Search

Navigation