Elsevier

Biomaterials

Volume 29, Issue 13, May 2008, Pages 2113-2124
Biomaterials

Dissolving microneedles for transdermal drug delivery

https://doi.org/10.1016/j.biomaterials.2007.12.048Get rights and content

Abstract

Microfabrication technology has been adapted to produce micron-scale needles as a safer and painless alternative to hypodermic needle injection, especially for protein biotherapeutics and vaccines. This study presents a design that encapsulates molecules within microneedles that dissolve within the skin for bolus or sustained delivery and leave behind no biohazardous sharp medical waste. A fabrication process was developed based on casting a viscous aqueous solution during centrifugation to fill a micro-fabricated mold with biocompatible carboxymethylcellulose or amylopectin formulations. This process encapsulated sulforhodamine B, bovine serum albumin, and lysozyme; lysozyme was shown to retain full enzymatic activity after encapsulation and to remain 96% active after storage for 2 months at room temperature. Microneedles were also shown to be strong enough to insert into cadaver skin and then to dissolve within minutes. Bolus delivery was achieved by encapsulating molecules just within microneedle shafts. For the first time, sustained delivery over hours to days was achieved by encapsulating molecules within the microneedle backing, which served as a controlled release reservoir that delivered molecules by a combination of swelling the backing with interstitial fluid drawn out of the skin and molecule diffusion into the skin via channels formed by dissolved microneedles. We conclude that dissolving microneedles can be designed to gently encapsulate molecules, insert into skin, and enable bolus or sustained release delivery.

Introduction

To address limitations of oral delivery and hypodermic injection [1], [2], [3], arrays of micron-scale needles have been developed to painlessly pierce skin's outer barrier of stratum corneum with the goal to deliver drugs with the efficacy of a needle and the convenience of a transdermal patch. This approach has demonstrated increased transdermal delivery of small-molecule drugs, proteins, DNA, and vaccines [4], [5]. One approach involves pretreatment of skin with microneedles, followed by application of a transdermal patch for extended drug delivery through the permeabilized skin [6]. Another approach involves coating or encapsulating drug onto or within microneedles. Upon dissolution of the coating or the needle itself, the drug cargo is released within the skin as a bolus or possible controlled release delivery [7], [8], [9], [10].

Microfabrication tools have been leveraged to make microneedles using methods suitable for low-cost, high-volume manufacturing, which is critical to impacting medicine as a disposable device. Microneedles suitable for piercing skin to increase skin permeability or for carrying drug into the skin as a coating have been fabricated from silicon and metal [4], [5]. Microneedles that encapsulate drug and subsequently dissolve or degrade in the skin have been fabricated from polymers, such as slow-degrading polylactic-co-glycolic acid [9] and rapidly dissolving sugar [8].

To address growing needs of protein delivery, we propose that a microneedle device should (1) encapsulate drug within a biocompatible and mechanically robust material using processes that do not damage protein integrity, (2) enable controlled delivery as a bolus or sustained release, and (3) utilize a device suitable for self-administration without medical training that leaves behind no sharp, biohazardous waste. This study presents microneedles designed to have these attributes using polysaccharide biomaterials; a gentle microneedle molding technique; and study of mechanical, stability, and delivery properties using model proteins and cadaver skin.

Section snippets

Molding

Micromolds were fabricated using photolithography and molding processes described previously [11]. In brief, a female microneedle master-mold was structured in SU-8 photoresist (SU-8 2025, Microchem, Newton, MA) by UV exposure to create conical (circular cross section) or pyramidal (square cross section) microneedles tapering from a base measuring 300 μm to a tip measuring 25 μm in width over a microneedle length of 600–800 μm. A male microneedle master-structure made of polydimethylsiloxane

Fabrication of dissolving microneedles

We identified 4 materials-related criteria to make microneedles for self-administration of biotherapeutics from a minimally invasive patch: (1) gentle fabrication to avoid damaging sensitive biomolecules, (2) sufficient mechanical strength for insertion into skin, (3) controlled release for bolus and sustained drug delivery, and (4) rapid dissolution of microneedles made of safe materials. Guided by these criteria, we selected 2 polysaccharides – i.e., carboxymethylcellulose and amylopectin –

Significance to drug delivery

Dissolving microneedles designed in this study may enable (1) bolus and sustained delivery of drugs into the skin, (2) self-administration of drugs that would otherwise require a hypodermic needle and (3) elimination of dangers associated with improper needle disposal and intentional re-use, especially in the developing world.

Previous studies that have developed microneedles that dissolve or degrade in the skin have either melted polymer into a mold at high temperature [8], [9], which can

Conclusion

This study presents a dissolving microneedle design involving fabrication under mild conditions that may be suitable for protein delivery and amenable to mass production. It was developed by selecting FDA-approved polysaccharides and modifying a casting method with centrifugation. By using a low aspect ratio and pyramidal geometry, dissolving microneedles were formulated to have sufficient mechanical strength to insert into skin. By selectively loading microneedle shafts, microneedle patches

Acknowledgments

We thank Dr. Seong-O Choi for providing microneedle master structures and Prof. Jianmin Qu for the helpful discussions. This work was supported in part by the National Institutes of Health and carried out at the Institute for Bioengineering and Bioscience and the Center for Drug Design, Development, and Delivery at the Georgia Institute of Technology. Mark Prausnitz is the Emerson–Lewis Faculty Fellow at Georgia Tech.

References (30)

  • L. Simonsen et al.

    Unsafe injections in the developing world and transmission of bloodborne pathogens: a review

    Bulletin of the World Health Organization

    (1999)
  • M.L. Reed et al.

    Microsystems for drug and gene delivery

    Proceedings of the IEEE

    (2004)
  • D.V. McAllister et al.

    Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: fabrication methods and transport studies

    Proceedings of the National Academy of Sciences of the United States of America

    (2003)
  • J.A. Matriano et al.

    Macroflux (R) microprojection array patch technology: a new and efficient approach for intracutaneous immunization

    Pharmaceutical Research

    (2002)
  • T. Miyano et al.

    Sugar micro needles as transdermic drug delivery system

    Biomedical Microdevices

    (2005)
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