The development and characteristics of novel microneedle arrays fabricated from hyaluronic acid, and their application in the transdermal delivery of insulin.

The aim of the present study was to develop novel insulin-loaded microneedle arrays (MNs) fabricated from hyaluronic acid (HA), and characterize their applicability in the transdermal delivery of insulin. The shape of MNs was observed via scanning electron microscopy. The characteristics of these novel insulin-loaded MNs, including hygroscopy, stability, drug release profiles, and dissolution properties, were evaluated from a clinical application point-of-view. Transepidermal water loss (TEWL) was measured to investigate the piercing properties of MNs, and the recovery of the skin barrier after the removal of MNs to confirm their safety. Additionally, the transdermal absorption of insulin from MNs was examined via an in vivo absorption study in diabetic rats. The length of MNs was 800 μm with a base diameter of 160 μm and a tip diameter of 40 μm. MNs were found to maintain their skin piercing abilities for at least 1h, even at a relative humidity of 75%. After storing insulin-loaded MNs for a month at -40, 4, 20, and 40 °C, more than 90% of insulin remained in MNs at all temperatures, indicating that insulin is highly stable in MNs at these storage conditions. It was also found that insulin is rapidly released from MNs via an in vitro release study. These findings were consistent with the complete dissolution of MNs within 1h of application to rat skin in vivo. Therefore, the novel HA MNs possess self-dissolving properties after their dermal application, and insulin appears to be rapidly released from these MNs. A significant increase in TEWL was observed after the application of MNs. However, this parameter recovered back to baseline within 24h after the removal of MNs. These findings indicate that the transdermal transport pathway of insulin, which was created by the MNs, disappeared within 24h, and that the skin damage induced by the MNs was reversible. Furthermore, a dose-dependent hypoglycemic effect and transdermal delivery of insulin were observed after a dermal treatment with insulin-loaded MNs in vivo. A continuous hypoglycemic effect was observed after 0.25 IU of insulin was administered to skin via MNs. Additionally, lower peak plasma insulin levels, but higher plasma insulin concentrations after 2 h, were achieved with 0.25 IU of insulin administered via MNs as compared to the subcutaneous administration of insulin of the same dose. Pharmacodynamic and pharmacokinetic parameters indicated that insulin administered via MNs was almost completely absorbed from the skin into the systemic circulation, and that the hypoglycemic effect of insulin-loaded MNs was almost similar to that of the subcutaneous injection of insulin. These findings indicate that the novel insulin-loaded MNs fabricated from HA are a very useful alternative method of delivering insulin via the skin into the systemic circulation without inducing serious skin damage. Therefore, HA MNs may be an effective and safe method of transdermal insulin delivery in the clinic.

[1]  J. Yoshimitsu,et al.  Self-dissolving microneedles for the percutaneous absorption of EPO in mice , 2006, Journal of drug targeting.

[2]  H. Katsumi,et al.  Transdermal delivery of insulin using trypsin as a biochemical enhancer. , 2008, Biological & pharmaceutical bulletin.

[3]  Tielin Shi,et al.  Iontophoresis-driven penetration of nanovesicles through microneedle-induced skin microchannels for enhancing transdermal delivery of insulin. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[4]  Göran Stemme,et al.  Painless Drug Delivery Through Microneedle-Based Transdermal Patches Featuring Active Infusion , 2008, IEEE Transactions on Biomedical Engineering.

[5]  H. Katsumi,et al.  Effects of polyamidoamine (PAMAM) dendrimers on the nasal absorption of poorly absorbable drugs in rats. , 2010, International journal of pharmaceutics.

[6]  T. Fujita,et al.  Improvement of pulmonary absorption of insulin and other water-soluble compounds by polyamines in rats. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[7]  M. Allen,et al.  Lack of Pain Associated with Microfabricated Microneedles , 2001, Anesthesia and analgesia.

[8]  A. Fahr,et al.  Skin penetration enhancement by a microneedle device (Dermaroller) in vitro: dependency on needle size and applied formulation. , 2009, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[9]  M. Garland,et al.  Laser-Engineered Dissolving Microneedle Arrays for Transdermal Macromolecular Drug Delivery , 2011, Pharmaceutical Research.

[10]  Kanji Takada,et al.  Feasibility of microneedles for percutaneous absorption of insulin. , 2006, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[11]  Mark G. Allen,et al.  Hollow metal microneedles for insulin delivery to diabetic rats , 2005, IEEE Transactions on Biomedical Engineering.

[12]  R. Guy,et al.  Assessment of Skin Barrier Function Using Transepidermal Water Loss: Effect of Age , 1989, Pharmaceutical Research.

[13]  H. Katsumi,et al.  Development of a novel self-dissolving microneedle array of alendronate, a nitrogen-containing bisphosphonate: evaluation of transdermal absorption, safety, and pharmacological effects after application in rats. , 2012, Journal of pharmaceutical sciences.

[14]  Takaya Miyano,et al.  Sugar Micro Needles as Transdermic Drug Delivery System , 2005, Biomedical microdevices.

[15]  Mark G. Allen,et al.  Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: Fabrication methods and transport studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[16]  D. Raccah,et al.  Alternatives routes of insulin delivery. , 2006, Diabetes & metabolism.

[17]  Jung-Hwan Park,et al.  Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery , 2004, The 26th Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[18]  T. Fujita,et al.  Pulmonary absorption enhancement of peptides by absorption enhancers and protease inhibitors , 1996 .

[19]  A. Banga,et al.  In vitro transdermal delivery of therapeutic antibodies using maltose microneedles. , 2009, International journal of pharmaceutics.

[20]  Akira Yamamoto,et al.  Penetration and enzymatic barriers to peptide and protein absorption , 1989 .

[21]  Peter McLoughlin,et al.  Microneedle mediated delivery of nanoparticles into human skin. , 2009, International journal of pharmaceutics.

[22]  C. Rosado,et al.  Modeling TEWL‐desorption curves: a new practical approach for the quantitative in vivo assessment of skin barrier , 2005, Experimental dermatology.

[23]  Mark G. Allen,et al.  Polymer Microneedles for Controlled-Release Drug Delivery , 2006, Pharmaceutical Research.

[24]  A. Morrissey,et al.  Clinical administration of microneedles: skin puncture, pain and sensation , 2009, Biomedical microdevices.

[25]  Regina Luttge,et al.  Silicon micromachined hollow microneedles for transdermal liquid transport , 2003 .

[26]  Mark R. Prausnitz,et al.  Effect of Microneedle Design on Pain in Human Volunteers , 2008, The Clinical journal of pain.

[27]  J. Bouwstra,et al.  In vivo assessment of safety of microneedle arrays in human skin. , 2008, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[28]  Göran Stemme,et al.  Novel Microneedle Patches for Active Insulin Delivery are Efficient in Maintaining Glycaemic Control: An Initial Comparison with Subcutaneous Administration , 2007, Pharmaceutical Research.

[29]  Conor O'Mahony,et al.  Processing difficulties and instability of carbohydrate microneedle arrays , 2009, Drug development and industrial pharmacy.

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

[31]  Manhee Han,et al.  Influence of the delivery systems using a microneedle array on the permeation of a hydrophilic molecule, calcein. , 2008, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[32]  J. Moan,et al.  Microneedle Pre-treatment of Human Skin Improves 5-Aminolevulininc Acid (ALA)- and 5-Aminolevulinic Acid Methyl Ester (MAL)-Induced PpIX Production for Topical Photodynamic Therapy Without Increase in Pain or Erythema , 2010, Pharmaceutical Research.

[33]  Jin-Lan Zhang,et al.  Transdermal delivery of insulin using microneedle rollers in vivo. , 2010, International journal of pharmaceutics.

[34]  Valérie Zuang,et al.  Follow-up to the ECVAM Prevalidation Study on In Vitro Tests for Acute Skin Irritation , 2002, Alternatives to laboratory animals : ATLA.

[35]  Dorian Liepmann,et al.  Clinical microneedle injection of methyl nicotinate: stratum corneum penetration , 2005, Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging.

[36]  Shankar Chandrasekaran,et al.  Surface micromachined metallic microneedles , 2003 .

[37]  S Diot,et al.  A prevalidation study on the in vitro skin irritation function test (SIFT) for prediction of acute skin irritation in vivo: results and evaluation of ECVAM Phase III. , 2003, Toxicology in vitro : an international journal published in association with BIBRA.

[38]  Chandra Sekhar Kolli,et al.  Characterization of Solid Maltose Microneedles and their Use for Transdermal Delivery , 2007, Pharmaceutical Research.

[39]  Xianhua Feng,et al.  Mechanical Properties of Polyelectrolyte Complex Films Based on Polyvinylamine and Carboxymethyl Cellulose , 2006 .

[40]  J. Bouwstra,et al.  Assembled microneedle arrays enhance the transport of compounds varying over a large range of molecular weight across human dermatomed skin. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[41]  Melissa Ai Ling Teo,et al.  In Vitro and In Vivo Characterization of MEMS Microneedles , 2005, Biomedical microdevices.

[42]  Guangjiong Qin,et al.  Sustained release of insulin through skin by intradermal microdelivery system , 2010, Biomedical microdevices.

[43]  Wijaya Martanto,et al.  Microinfusion Using Hollow Microneedles , 2006, Pharmaceutical Research.

[44]  Wijaya Martanto,et al.  Transdermal Delivery of Insulin Using Microneedles in Vivo , 2004, Pharmaceutical Research.

[45]  Michael L. Reed,et al.  Microsystems for drug and gene delivery , 2004, Proceedings of the IEEE.

[46]  Mark R Prausnitz,et al.  Precise microinjection into skin using hollow microneedles. , 2006, The Journal of investigative dermatology.

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

[48]  Henry,et al.  Microfabricated microneedles: A novel approach to transdermal drug delivery , 1999, Journal of pharmaceutical sciences.