Pharmaceutical Research

, Volume 23, Issue 5, pp 1008–1019 | Cite as

Polymer Microneedles for Controlled-Release Drug Delivery

  • Jung-Hwan Park
  • Mark G. Allen
  • Mark R. Prausnitz
Research Paper


As an alternative to hypodermic injection or implantation of controlled-release systems, this study designed and evaluated biodegradable polymer microneedles that encapsulate drug for controlled release in skin and are suitable for self-administration by patients.


Arrays of microneedles were fabricated out of poly-lactide-co-glycolide using a mold-based technique to encapsulate model drugs—calcein and bovine serum albumin (BSA)—either as a single encapsulation within the needle matrix or as a double encapsulation, by first encapsulating the drug within carboxymethylcellulose or poly-l-lactide microparticles and then encapsulating drug-loaded microparticles within needles.


By measuring failure force over a range of conditions, poly-lactide-co-glycolide microneedles were shown to exhibit sufficient mechanical strength to insert into human skin. Microneedles were also shown to encapsulate drug at mass fractions up to 10% and to release encapsulated compounds within human cadaver skin. In vitro release of calcein and BSA from three different encapsulation formulations was measured over time and was shown to be controlled by the encapsulation method to achieve release kinetics ranging from hours to months. Release was modeled using the Higuchi equation with good agreement (r 2 ≥ 0.90). After microneedle fabrication at elevated temperature, up to 90% of encapsulated BSA remained in its native state, as determined by measuring effects on primary, secondary, and tertiary protein structure.


Biodegradable polymer microneedles can encapsulate drug to provide controlled-release delivery in skin for hours to months.

Key Words

controlled-release drug delivery microneedles protein stability transdermal drug delivery 



We thank Jin-Woo Park, Hak-Jun Sung, and Ping Ming Wang for helpful discussions and Gary Meek for photographing Fig. 3F. This work was supported in part by the National Institutes of Health. J.-H. P., M. G. A., and M. R. P. are members of the Microelectronics Research Center, and J.-H. P. and M. R. P. are members of the Institute for Bioengineering and Bioscience and the Center for Drug Design, Development and Delivery at Georgia Tech.


  1. 1.
    Langer, R. 1998Drug delivery and targetingNature392510PubMedGoogle Scholar
  2. 2.
    Rosen, H., Abribat, T. 2005The rise and rise of drug deliveryNat. Rev. Drug Discov.4381385PubMedCrossRefGoogle Scholar
  3. 3.
    Periti, P., Mazzei, T., Mini, E. 2002Clinical pharmacokinetics of depot leuprorelinClin. Pharmacokinet.41485504PubMedCrossRefGoogle Scholar
  4. 4.
    Brem, H., Piantadosi, S., Burger, P. C., Walker, M., Selker, R., Vick, N. A., Black, K., Sisti, M., Brem, S., Mohr, G.,  et al. 1995Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-Brain Tumor Treatment GroupLancet34510081012PubMedCrossRefGoogle Scholar
  5. 5.
    Kaushik, S., Hord, A. H., Denson, D. D., McAllister, D. V., Smitra, S., Allen, M. G., Prausnitz, M. R. 2001Lack of pain associated with microfabricated microneedlesAnesth. Analg.92502504PubMedCrossRefGoogle Scholar
  6. 6.
    Mikszta, J. A., Alarcon, J. B., Brittingham, J. M., Sutter, D. E., Pettis, R. J., Harvey, N. G. 2002Improved genetic immunization via micromechanical disruption of skin-barrier function and targeted epidermal deliveryNat. Med.8415419PubMedCrossRefGoogle Scholar
  7. 7.
    Henry, S., McAllister, D., Allen, M. G., Prausnitz, M. R. 1998Microfabricated microneedles: a novel method to increase transdermal drug deliveryJ. Pharm. Sci.87922925PubMedCrossRefGoogle Scholar
  8. 8.
    Cormier, M., Johnson, B., Ameri, M., Nyam, K., Libiran, L., Zhang, D. D., Daddona, P. 2004Transdermal delivery of desmopressin using a coated microneedle array patch systemJ. Control. Release97503511PubMedGoogle Scholar
  9. 9.
    Miyano, T., Tobinaga, Y., Kanno, T., Matsuzaki, Y., Takeda, H., Wakui, M., Hanada, K. 2005Sugar micro needles as transdermic drug delivery systemBiomed. Microdevices7185188PubMedCrossRefGoogle Scholar
  10. 10.
    Prausnitz, M. R. 2004Microneedles for transdermal drug deliveryAdv. Drug Deliv. Rev.56581587PubMedCrossRefGoogle Scholar
  11. 11.
    Prausnitz, M., Mikszta, J., Raeder-Devens, J. 2005


    Smith, E.Maibach, H. eds. Percutaneous Penetration EnhancersCRCBoca Raton, FL239255
    Google Scholar
  12. 12.
    Gardeniers, J. G. E., Luttge, R., Berenschot, J. W., Boer, M. J., Yeshurun, Y., Hefetz, M., Oever, R., Berg, A. 2003Silicon micromachined hollow microneedles for transdermal liquid transportJ. MEMS6855862Google Scholar
  13. 13.
    McAllister, D. V., Wang, P. M., Davis, S. P., Park, J.-H., Canatella, P. J., Allen, M. G., Prausnitz, M. R. 2003Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: fabrication methods and transport studiesProc. Natl. Acad. Sci. USA1001375513760PubMedCrossRefGoogle Scholar
  14. 14.
    Sivamani, R. K., Stoeber, B., Wu, G. C., Zhai, H., Liepmann, D., Maibach, H. 2005Clinical microneedle injection of methyl nicotinate: stratum corneum penetrationSkin Res. Technol.11152156PubMedCrossRefGoogle Scholar
  15. 15.
    J. H. Park, S. P. Davis, Y. K. Yoon, M. R. Prausnitz, and M. G. Allen. Micromachined biodegradable microstructures. In The 16th Annual International Conference on Micro Electro Mechanical Systems, IEEE, Piscataway, NJ, 2003, pp. 371–374.Google Scholar
  16. 16.
    Davis, S. P., Landis, B. J., Adams, Z. H., Allen, M. G., Prausnitz, M. R. 2004Insertion of microneedles into skin: measurement and prediction of insertion force and needle fracture forceJ. Biomech.3711551163PubMedCrossRefGoogle Scholar
  17. 17.
    Saltzman, W. M. 2001Drug Delivery: Engineering Principles for Drug TherapyOxford University PressNew YorkGoogle Scholar
  18. 18.
    Kanjickal, D. G., Lopina, S. T. 2004Modeling of drug release from polymeric delivery systems—a reviewCrit. Rev. Ther. Drug Carr. Syst.21345386CrossRefGoogle Scholar
  19. 19.
    Madou, M. J. 2002Fundamentals of Microfabrication: The Science of MiniaturizationCRCBoca Raton, FLGoogle Scholar
  20. 20.
    Park, J.-H., Allen, M. G., Prausnitz, M. R. 2005Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug deliveryJ. Control. Release1045166PubMedCrossRefGoogle Scholar
  21. 21.
    Lee, H. K., Park, J. H., Kwon, K. C. 1997Double-walled microparticles for single shot vaccineJ. Control. Release44283293CrossRefGoogle Scholar
  22. 22.
    Benoit, J.-P., Marchais, H., Rolland, H., Velde, V. V. 1996

    Biodegradable microspheres: advances in production technology

    Benita, S. eds. MicroencapsulationMarcel DekkerNew York3572
    Google Scholar
  23. 23.
    Gupta, R. K., Chang, A. C., Griffin, P., Rivera, R., Guo, Y. Y., Siber, G. R. 1997Determination of protein loading in biodegradable polymer microspheres containing tetanus toxoidVaccine15672678PubMedCrossRefGoogle Scholar
  24. 24.
    Y. W. Chien (ed.), Novel Drug Delivery Systems: Fundamentals, Developmental Concepts, Biomedical Assessments, Marcel Dekker, New York, 1991.Google Scholar
  25. 25.
    Baker, R. W., Lonsdale, H. K. 1974

    Controlled release: mechanisms and rates

    Tanquary, A. C.Lacey, R. E. eds. Controlled Release of Biologically Active Agents. Advances in Experimental Medicine and Biology, Vol. 47PlenumNew York1572
    Google Scholar
  26. 26.
    Faisant, N., Siepmann, J., Benoit, J. P. 2002PLGA-based microparticles: elucidation of mechanisms and a new, simple mathematical model quantifying drug releaseEur. J. Pharm. Sci.15355366PubMedCrossRefGoogle Scholar
  27. 27.
    Bulone, D., Martorana, V., Biagio, P. L. 2001Effects of intermediates on aggregation of native bovine serum albuminBiophys. Chem.916169PubMedCrossRefGoogle Scholar
  28. 28.
    Liu, W. R., Langer, R., Klibanov, A. M. 1991Moisture-induced aggregation of lyophilized proteins in the solid stateBiotechnol. Bioeng.37177184CrossRefGoogle Scholar
  29. 29.
    Lowry, O. H., Rosebrough, N. J., Farr, A. L., Randall, R. J. 1951Protein measurement with the Folin phenol reagentJ. Biol. Chem.193265275PubMedGoogle Scholar
  30. 30.
    Berne, B. J., Pecora, R. 2000Dynamic Light Scattering: With Applications to Chemistry, Biology, and PhysicsDover PublicationsMineola, NYGoogle Scholar
  31. 31.
    G. D. Fasman (ed.). Circular Dichroism and the Conformational Analysis of Biomolecules. Plenum, New York, 1996.Google Scholar
  32. 32.
    Lu, L., Garcia, C. A., Mikos, A. G. 1999 In vitro degradation of thin poly(DL-lactic-co-glycolic acid) filmsJ. Biomed. Mater. Res.46236244PubMedCrossRefGoogle Scholar
  33. 33.
    K. Park (ed.), Controlled Drug Delivery: Challenges and Strategies. American Chemical Society, Washington, DC, 1997.Google Scholar
  34. 34.
    Monteiro-Riviere, N. A. 1991

    Comparative anatomy, physiology, and biochemistry of mammalian skin

    Hobson, D. W. eds. Dermal and Ocular ToxicologyCRCBoca Raton, FL371
    Google Scholar
  35. 35.
    Rousche, P. J., Normann, R. A. 1992A method for pneumatically inserting an array of penetrating electrodes into cortical tissueAnn. Biomed. Eng.20413422PubMedCrossRefGoogle Scholar
  36. 36.
    Yang, M., Zahn, J. D. 2004Microneedle insertion force reduction using vibratory actuationBiomed. Microdevices6177182PubMedCrossRefGoogle Scholar
  37. 37.
    Arakawa, T., Prestrelski, S. J., Kenney, W. C., Carpenter, J. F. 2001Factors affecting short-term and long-term stabilities of proteinsAdv. Drug Deliv. Rev.46307326PubMedCrossRefGoogle Scholar
  38. 38.
    Prausnitz, M. R., Mitragotri, S., Langer, R. 2004Current status and future potential of transdermal drug deliveryNat. Rev. Drug Discov.3115124PubMedCrossRefGoogle Scholar
  39. 39.
    Physicians' Desk Reference. Thomson PDR, Montvale, NJ, 2005.Google Scholar
  40. 40.
    Mitragotri, S. 2005Immunization without needlesNat. Rev. Immunol.5905916PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Jung-Hwan Park
    • 1
  • Mark G. Allen
    • 2
  • Mark R. Prausnitz
    • 1
    • 3
  1. 1.Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory UniversityGeorgia Institute of TechnologyAtlantaUSA
  2. 2.School of Electrical and Computer EngineeringGeorgia Institute of TechnologyAtlantaUSA
  3. 3.School of Chemical and Biomolecular EngineeringGeorgia Institute of TechnologyAtlantaUSA

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