Multilayered pyramidal dissolving microneedle patches with flexible pedestals for improving effective drug delivery

Abstract Dissolving microneedles have been employed as a safe and convenient transdermal delivery system for drugs and vaccines. To improve effective drug delivery, a multilayered pyramidal dissolving microneedle patch, composed of silk fibroin tips with the ability of robust mechanical strength, rapid dissolution and drug release supported on a flexible polyvinyl alcohol (PVA) pedestal is reported. To show the utility of this approach the ability of the fabricated microneedles to deliver insulin is demonstrated. The dissolving microneedles have sufficient mechanical strength to be inserted into abdomen skin of mice to a depth of approximately 150 &mgr;m, and release their encapsulated insulin into the skin to cause a hypoglycemic effect. The fabrication of microneedles avoids high temperature which benefits storage stability at room temperature for 20 d. This result indicates > 99.4% of insulin remained in the microneedles. In comparison to traditional needle‐based administration, the proposed multilayered pyramidal dissolving microneedle patches enable self‐administration, miniaturization, pain‐free administration, drug delivery and drug stability, all being important features in needle free drug delivery. Graphical abstract Figure. No Caption available.

[1]  Wolfgang Drexler,et al.  In Vivo, In Situ Imaging of Microneedle Insertion into the Skin of Human Volunteers Using Optical Coherence Tomography , 2010, Pharmaceutical Research.

[2]  Jung-Hwan Park,et al.  Dissolving microneedles for transdermal drug delivery. , 2008, Biomaterials.

[3]  M. Prausnitz,et al.  Immunization by vaccine-coated microneedle arrays protects against lethal influenza virus challenge , 2009, Proceedings of the National Academy of Sciences.

[4]  M. Prausnitz,et al.  Measles vaccination using a microneedle patch. , 2013, Vaccine.

[5]  M. Prausnitz,et al.  Delivery of subunit influenza vaccine to skin with microneedles improves immunogenicity and long-lived protection , 2012, Scientific Reports.

[6]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[7]  David L Kaplan,et al.  Physical and chemical aspects of stabilization of compounds in silk , 2012, Biopolymers.

[8]  David L Kaplan,et al.  Silk fibroin biomaterials for controlled release drug delivery , 2011, Expert opinion on drug delivery.

[9]  D. Kaplan,et al.  Materials fabrication from Bombyx mori silk fibroin , 2011, Nature Protocols.

[10]  Thomas Hankemeier,et al.  Novel Hollow Microneedle Technology for Depth-Controlled Microinjection-Mediated Dermal Vaccination: A Study with Polio Vaccine in Rats , 2014, Pharmaceutical Research.

[11]  Mark R Prausnitz,et al.  Minimally Invasive Protein Delivery with Rapidly Dissolving Polymer Microneedles , 2008, Advanced materials.

[12]  Mei-Chin Chen,et al.  Poly-γ-glutamic acid microneedles with a supporting structure design as a potential tool for transdermal delivery of insulin. , 2015, Acta biomaterialia.

[13]  David L Kaplan,et al.  Stabilization of vaccines and antibiotics in silk and eliminating the cold chain , 2012, Proceedings of the National Academy of Sciences.

[14]  Mark R Prausnitz,et al.  Microneedles for transdermal drug delivery. , 2004, Advanced drug delivery reviews.

[15]  Paula T Hammond,et al.  Composite Dissolving Microneedles for Coordinated Control of Antigen and Adjuvant Delivery Kinetics in Transcutaneous Vaccination , 2012, Advanced functional materials.

[16]  J. Stockman,et al.  Dissolving polymer microneedle patches for influenza vaccination , 2012 .

[17]  P. R. Miller,et al.  Microneedle-based self-powered glucose sensor , 2014 .

[18]  Mei-Chin Chen,et al.  Dissolving polymer microneedle patches for rapid and efficient transdermal delivery of insulin to diabetic rats. , 2013, Acta biomaterialia.

[19]  D. Kaplan,et al.  Silk-based delivery systems of bioactive molecules. , 2010, Advanced drug delivery reviews.

[20]  Yeu‐Chun Kim,et al.  Microneedle patches for vaccine delivery , 2013, Clinical and experimental vaccine research.

[21]  Akira Yamamoto,et al.  The development and characteristics of novel microneedle arrays fabricated from hyaluronic acid, and their application in the transdermal delivery of insulin. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[22]  Ashish A. Pandya,et al.  Rapidly–Dissolvable Microneedle Patches Via a Highly Scalable and Reproducible Soft Lithography Approach , 2013, Advanced materials.

[23]  Paula T Hammond,et al.  Implantable Silk Composite Microneedles for Programmable Vaccine Release Kinetics and Enhanced Immunogenicity in Transcutaneous Immunization , 2013, Advanced healthcare materials.

[24]  Keizo Fukushima,et al.  Two-layered dissolving microneedles formulated with intermediate-acting insulin. , 2012, International journal of pharmaceutics.

[25]  M. Prausnitz,et al.  A microneedle patch containing measles vaccine is immunogenic in non-human primates. , 2015, Vaccine.

[26]  M. Prausnitz,et al.  Inactivated polio vaccination using a microneedle patch is immunogenic in the rhesus macaque. , 2015, Vaccine.

[27]  Thakur Raghu Raj Singh,et al.  Optical coherence tomography is a valuable tool in the study of the effects of microneedle geometry on skin penetration characteristics and in-skin dissolution. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[28]  Ran Liu,et al.  In vivo and in situ imaging of controlled‐release dissolving silk microneedles into the skin by optical coherence tomography , 2017, Journal of biophotonics.

[29]  Ning Wang,et al.  Mannosylated and lipid A-incorporating cationic liposomes constituting microneedle arrays as an effective oral mucosal HBV vaccine applicable in the controlled temperature chain. , 2015, Colloids and surfaces. B, Biointerfaces.