Transdermal delivery of relatively high molecular weight drugs using novel self-dissolving microneedle arrays fabricated from hyaluronic acid and their characteristics and safety after application to the skin.

The purpose of this study was to develop novel dissolving microneedle arrays fabricated from hyaluronic acid (HA) as a material and to improve the transdermal permeability of relatively high molecular weight drugs. In this study, fluorescein isothiocyanate-labeled dextran with an average molecular weight of 4kDa (FD4) was used as a model drug with a relatively high molecular weight. The microneedle arrays significantly increased transepidermal water loss (TEWL) and reduced transcutaneous electrical resistance (TER), indicating that they could puncture the skin and create drug permeation pathways successfully. Both TEWL and TER almost recovered to baseline levels in the microneedle array group, and relatively small pathways created by the microneedles rapidly recovered as compared with those created by a tape stripping treatment. These findings confirmed that the microneedle arrays were quite safe. Furthermore, we found that the transdermal permeability of FD4 using the microneedle arrays was much higher than that of the FD4 solution. Furthermore, we found that the microneedle arrays were much more effective for increasing the amount of FD4 accumulated in the skin. These findings indicated that using novel microneedle arrays fabricated from HA is a very useful and effective strategy to improve the transdermal delivery of drugs, especially relatively high molecular weight drugs without seriously damaging the skin.

[1]  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.

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

[3]  Petras Juzenas,et al.  Microneedle-mediated intradermal delivery of 5-aminolevulinic acid: potential for enhanced topical photodynamic therapy. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[4]  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.

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

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

[7]  Wijaya Martanto,et al.  Mechanism of fluid infusion during microneedle insertion and retraction. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[8]  Tatsuma Yamamoto,et al.  Electrical properties of the epidermal stratum corneum , 2006, Medical and biological engineering.

[9]  Nicole Ferko,et al.  Prediction of falls using a risk assessment tool in the acute care setting , 2004, BMC medicine.

[10]  H. Maibach,et al.  A functional study of the skin barrier to evaporative water loss by means of repeated cellophane‐tape stripping , 1990, Clinical and experimental dermatology.

[11]  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.

[12]  J. Heylings,et al.  Multi-species assessment of electrical resistance as a skin integrity marker for in vitro percutaneous absorption studies. , 2004, Toxicology in vitro : an international journal published in association with BIBRA.

[13]  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.

[14]  Jung-Hwan Park,et al.  Microneedles for drug and vaccine delivery. , 2012, Advanced drug delivery reviews.

[15]  Jie Zhang,et al.  Evaluation needle length and density of microneedle arrays in the pretreatment of skin for transdermal drug delivery. , 2010, International journal of pharmaceutics.

[16]  Seung S. Lee,et al.  Mass producible and biocompatible microneedle patch and functional verification of its usefulness for transdermal drug delivery , 2009, Biomedical microdevices.

[17]  Mark R. Prausnitz,et al.  Coating Formulations for Microneedles , 2007, Pharmaceutical Research.

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

[19]  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.

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

[21]  J. Birchall,et al.  Gene Delivery to the Epidermal Cells of Human Skin Explants Using Microfabricated Microneedles and Hydrogel Formulations , 2008, Pharmaceutical Research.

[22]  John H. Draize,et al.  METHODS FOR THE STUDY OF IRRITATION AND TOXICITY OF SUBSTANCES APPLIED TOPICALLY TO THE SKIN AND MUCOUS MEMBRANES , 1944 .

[23]  A. Banga,et al.  Enhanced transdermal delivery of low molecular weight heparin by barrier perturbation. , 2009, International journal of pharmaceutics.

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

[25]  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.

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

[27]  Scott A. Kaestner,et al.  Microneedle-Based Intradermal Delivery Enables Rapid Lymphatic Uptake and Distribution of Protein Drugs , 2010, Pharmaceutical Research.

[28]  Yukako Ito,et al.  Incidence of low bioavailability of leuprolide acetate after percutaneous administration to rats by dissolving microneedles. , 2011, International journal of pharmaceutics.

[29]  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.

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

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

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

[33]  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.

[34]  Ajay K Banga,et al.  Microneedles and their applications. , 2011, Recent patents on drug delivery & formulation.

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

[36]  Michael S Roberts,et al.  Dry-coated microprojection array patches for targeted delivery of immunotherapeutics to the skin. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

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

[38]  L. Yang,et al.  Topical stratum corneum lipids accelerate barrier repair after tape stripping, solvent treatment and some but not all types of detergent treatment , 1995, The British journal of dermatology.

[39]  Mark R Prausnitz,et al.  Coated microneedles for transdermal delivery. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

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

[41]  Mark R. Prausnitz,et al.  Dissolving Polymer Microneedle Patches for Influenza Vaccination , 2010, Nature Medicine.

[42]  Ryan F. Donnelly,et al.  Design, Optimization and Characterisation of Polymeric Microneedle Arrays Prepared by a Novel Laser-Based Micromoulding Technique , 2010, Pharmaceutical Research.

[43]  S. González,et al.  Transdermal microconduits by microscission for drug delivery and sample acquisition , 2004, BMC medicine.

[44]  Jung-Hwan Park,et al.  Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[45]  Jim Euchner Design , 2014, Catalysis from A to Z.

[46]  Bai Xu,et al.  Controlled transdermal delivery of model drug compounds by MEMS microneedle array. , 2005, Nanomedicine : nanotechnology, biology, and medicine.

[47]  Mark R Prausnitz,et al.  Kinetics of skin resealing after insertion of microneedles in human subjects. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[48]  M Gloor,et al.  Testing for irritation with a multifactorial approach: comparison of eight non‐invasive measuring techniques on five different irritation types , 2001, The British journal of dermatology.

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

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