Pocketed microneedles for drug delivery to the skin

Gill, Harvinder Singh; Prausnitz, Mark R.

doi:10.1016/j.jpcs.2007.10.059

Cited by 63 publications

(36 citation statements)

References 5 publications

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“…Although shown to be stable during storage for up to months, these coatings can dissolve off microneedles within the skin on a time scale of seconds. Using this approach, various model compounds, including proteins, DNA and viruses, have been coated and delivered to the skin in vitro; a model vaccine, ovalbumin (OVA), has also been delivered to animals in vivo, as discussed below [18, 29–31, 37, 54, 80, 92, 97]. …”

Section: Microneedle Designs and Delivery Conceptsmentioning

confidence: 99%

Microneedle-Based Vaccines

Prausnitz

Mikszta

Cormier³

et al. 2009

Current Topics in Microbiology and Immunology

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221

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The threat of pandemic influenza and other public health needs motivates development of better vaccine delivery systems. To address this need, microneedles have been developed as micron-scale needles fabricated using low-cost manufacturing methods that administer vaccine into the skin using a simple device that may be suitable for self-administration. Delivery using solid or hollow microneedles can be accomplished by (i) piercing the skin and then applying a vaccine formulation or patch onto the permeabilized skin, (ii) coating or encapsulating vaccine onto or within microneedles for rapid, or delayed, dissolution and release in the skin and (iii) injection into the skin using a modified syringe or pump. Extensive clinical experience with smallpox, TB and other vaccines has shown that vaccine delivery into the skin using conventional intradermal injection is generally safe and effective and often elicits the same immune responses at lower doses compared to intramuscular injection. Animal experiments using microneedles have shown similar benefits. Microneedles have been used to deliver whole, inactivated virus; trivalent split antigen vaccines; and DNA plasmid encoding the influenza hemagglutinin to rodents and found strong antibody responses. In addition, ChimeriVax™-JE against yellow fever was administered to non-human primates and generated protective levels of neutralizing antibodies more than seven times greater than subcutaneous delivery; DNA plasmid encoding hepatitis B surface antigen was administered to mice and generated antibody and T cell responses at least as strong as hypodermic injections; recombinant Protective Antigen of Baccilus anthracis was administered to rabbits and provided complete protection from lethal aerosol anthrax spore challenge at a lower dose than intramuscular injection; and DNA plasmid encoding four vaccinia virus genes administered to mice in combination with electroporation generated neutralizing antibodies that apparently included both Th1 and Th2 responses. Dose sparing with microneedles was specifically studied in mice with the model vaccine ovalbumin. At low dose (1 µg), specific antibody titers from microneedles were one order of magnitude greater than subcutaneous injection and two orders of magnitude greater than intramuscular injection. At higher doses, antibody responses increased for all delivery methods. At the highest levels (20-80 µg), the route of administration had no significant effect on the immune response. Concerning safety, no infections or other serious adverse events have been observed in well over 1000 microneedle insertions in human and animal subjects. Bleeding generally does not occur for short microneedles (<1 mm). Highly localized, mild and transient erythema is often observed. Microneedle pain has been reported as non-existent to mild, and always much less than a hypodermic needle control. Overall, these studies suggest that microneedles may provide a safe and NIH Public Access

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Section: Microneedle Designs and Delivery Conceptsmentioning

confidence: 99%

Microneedle-Based Vaccines

Prausnitz

Mikszta

Cormier³

et al. 2009

Current Topics in Microbiology and Immunology

Self Cite

221

218

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“…Experiments with human volunteers demonstrated very low pain scores from microneedle application as compared to hypodermic needles, and fast skin resealing after removal of microneedles [17–20]. …”

Section: Introductionmentioning

confidence: 99%

Improved immunogenicity of individual influenza vaccine components delivered with a novel dissolving microneedle patch stable at room temperature

Vassilieva

Kalluri

McAllister

et al. 2015

Drug Deliv. and Transl. Res.

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Prevention of seasonal influenza epidemics and pandemics relies on widespread vaccination coverage to induce protective immunity. In addition to a good antigenic match with the circulating viruses, the effectiveness of individual strains represented in the trivalent vaccines depends on their immunogenicity. In this study we evaluated the immunogenicity of H1N1, H3N2 and B seasonal influenza virus vaccine strains delivered individually with a novel dissolving microneedle patch and the stability of this formulation during storage at 25°C. Our data demonstrate that all strains retained their antigenic activity after incorporation in the dissolving patches as measured by SRID assay and immune responses to vaccination in BALB/c mice. After a single immunization all three antigens delivered with microneedle patches induced superior neutralizing antibody titers compared to intramuscular immunization. Cutaneous antigen delivery was especially beneficial for the less immunogenic B strain. Mice immunized with dissolving microneedle patches encapsulating influenza A/Brisbane/59/07 (H1N1) vaccine were fully protected against lethal challenge by homologous mouse-adapted influenza virus. All vaccine components retained activity during storage at room temperature for at least three months as measured in vitro by SRID assay and in vivo by mouse immunization studies. Our data demonstrate that dissolving microneedle patches are a promising advance for influenza cutaneous vaccination due to improved immune responses using less immunogenic influenza antigens and enhanced stability.

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“…To develop a uniform coating of the recombinant 4.M2-tFliC on MNs, a microprecision dip-coating process was used as described previously [34, 35]. The coating solution was composed of excipients including 1% (w/v) carboxymethylcellulose sodium salt (low viscosity, USP grade, CarboMer, San Diego, CA, USA), 0.5% (w/v) Lutrol F-68 NF (BASF, Mt.…”

Section: Methodsmentioning

confidence: 99%

Microneedle delivery of an M2e-TLR5 ligand fusion protein to skin confers broadly cross-protective influenza immunity

Wang

Gill

et al. 2014

Journal of Controlled Release

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Influenza vaccines with broad cross-protection are urgently needed to prevent an emerging influenza pandemic. A fusion protein of the TLR5-agonist domains from flagellin and multiple repeats of the conserved extracellular domain of the influenza matrix protein 2 (M2e) was constructed, purified and evaluated as such a vaccine. A painless vaccination method suitable for possible self-administration using coated microneedle arrays was investigated for skin-targeted delivery of the fusion protein in a mouse model. The results demonstrate that microneedle immunization induced strong humoral as well as mucosal antibody responses and conferred complete protection against homo- and heterosubtypic lethal virus challenges. Protective efficacy with microneedles was found to be significantly better than that seen with conventional intramuscular injection, and comparable to that observed with intranasal immunization. Because of its advantages for administration, safety and storage, microneedle delivery of M2e-flagellin fusion protein is a promising approach for an easy-to-administer universal influenza vaccine.

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Pocketed microneedles for drug delivery to the skin

Cited by 63 publications

References 5 publications

Microneedle-Based Vaccines

Microneedle-Based Vaccines

Improved immunogenicity of individual influenza vaccine components delivered with a novel dissolving microneedle patch stable at room temperature

Microneedle delivery of an M2e-TLR5 ligand fusion protein to skin confers broadly cross-protective influenza immunity

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