Dissolving Polymer Microneedle Patches for Influenza Vaccination

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Abstract

Influenza prophylaxis would benefit from a vaccination method enabling simplified logistics and improved immunogenicity without the dangers posed by hypodermic needles. Here, we introduce dissolving microneedle patches for influenza vaccination using a simple patch-based system that targets delivery to skin’s antigen-presenting cells. Microneedles were fabricated using a biocompatible polymer encapsulating inactivated influenza virus vaccine for insertion and dissolution in the skin within minutes. Microneedle vaccination generated robust antibody and cellular immune responses in mice that provided complete protection against lethal challenge. Compared to conventional intramuscular injection, microneedle vaccination resulted in more efficient lung virus clearance and enhanced cellular recall responses after challenge. These results suggest that dissolving microneedle patches can provide a novel technology for simpler and safer vaccination with improved immunogenicity that could facilitate increased vaccination coverage.

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Most cited references 37

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Transdermal drug delivery.

Mark Prausnitz, Robert (Bob) Langer (2008)

Transdermal drug delivery has made an important contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. First-generation transdermal delivery systems have continued their steady increase in clinical use for delivery of small, lipophilic, low-dose drugs. Second-generation delivery systems using chemical enhancers, noncavitational ultrasound and iontophoresis have also resulted in clinical products; the ability of iontophoresis to control delivery rates in real time provides added functionality. Third-generation delivery systems target their effects to skin's barrier layer of stratum corneum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound. Microneedles and thermal ablation are currently progressing through clinical trials for delivery of macromolecules and vaccines, such as insulin, parathyroid hormone and influenza vaccine. Using these novel second- and third-generation enhancement strategies, transdermal delivery is poised to significantly increase its impact on medicine.

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Dissolving microneedles for transdermal drug delivery.

Jeong Lee, Jung-Hwan Park, Mark Prausnitz (2008)

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.

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Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery.

Jung-Hwan Park, Mark Allen, Mark Prausnitz (2005)

To overcome the skin's barrier properties that block transdermal delivery of most drugs, arrays of microscopic needles have been microfabricated primarily out of silicon or metal. This study addresses microneedles made of biocompatible and biodegradable polymers, which are expected to improve safety and manufacturability. To make biodegradable polymer microneedles with sharp tips, micro-electromechanical masking and etching were adapted to produce beveled- and chisel-tip microneedles and a new fabrication method was developed to produce tapered-cone microneedles using an in situ lens-based lithographic approach. To replicate microfabricated master structures, PDMS micromolds were generated and a novel vacuum-based method was developed to fill the molds with polylactic acid, polyglycolic acid, and their co-polymers. Mechanical testing of the resulting needles measured the force at which needles broke during axial loading and found that this failure force increased with Young's modulus of the material and needle base diameter and decreased with needle length. Failure forces were generally much larger than the forces needed to insert microneedles into skin, indicating that biodegradable polymers can have satisfactory mechanical properties for microneedles. Finally, arrays of polymer microneedles were shown to increase permeability of human cadaver skin to a low-molecular weight tracer, calcein, and a macromolecular protein, bovine serum albumin, by up to three orders of magnitude. Altogether, these results indicate that biodegradable polymer microneedles can be fabricated with an appropriate geometry and sufficient strength to insert into skin, and thereby dramatically increase transdermal transport of molecules.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9502015

Journal ID (pubmed-jr-id): 8791

Journal ID (nlm-ta): Nat Med

Title: Nature medicine

ISSN (Print): 1078-8956

ISSN (Electronic): 1546-170X

Publication date Nihms-submitted: 29 April 2010

Publication date (Electronic): 18 July 2010

Publication date (Print): August 2010

Publication date PMC-release: 1 February 2011

Volume: 16

Issue: 8

Pages: 915-920

Affiliations

[1 ] Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Tech, Georgia Institute of Technology, Atlanta, GA, 30332

[2 ] Department of Microbiology & Immunology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, 30322

[3 ] School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, 30332

Author notes

[* ]To whom correspondence should be addressed: prausnitz@ 123456gatech.edu (MRP), iskount@ 123456emory.edu (IS)

[#]

These authors contributed equally to this work

Article

Manuscript ID: nihpa199346

DOI: 10.1038/nm.2182

PMC ID: 2917494

PubMed ID: 20639891

SO-VID: a94e371c-60dd-45e4-b84a-490589f5dcdc

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