Self-Dissolving Microneedle Arrays for Transdermal Absorption Enhancement of Human Parathyroid Hormone (1-34)

Human parathyroid hormone (1-34) (PTH) has been widely used as the subcutaneous injection formulation for the treatment of osteoporosis. In the present study, we developed an efficient transdermal delivery system of PTH by using dissolving microneedle arrays (MNs) composed of hyaluronic acid (HA) for the treatment of osteoporosis. PTH-loaded MNs, with needle length 800 µm, were fabricated via a micro-molding method. The stability of PTH in MNs was found to be 6-fold higher than that of PTH solution when stored at room temperature (15–20 °C) for one month. Micron-scale pores were clearly visible in rat skin following application of PTH-loaded MNs. PTH-loaded MNs were completely dissolved by 60 min following application to rat skin. The bioavailability (BA) of PTH relative to subcutaneous injection was 100 ± 4% following application of PTH-loaded MNs in rats. In addition, PTH-loaded MNs were found to effectively suppress decreases in bone density in a rat model of osteoporosis. Furthermore, no skin irritation was observed at the site of application in rats. These findings indicate that our dissolving MNs have a potential use in formulations for the transdermal delivery of PTH and for the treatment of osteoporosis.

[1]  H. Katsumi,et al.  Permeation of sumatriptan succinate across human skin using multiple types of self-dissolving microneedle arrays fabricated from sodium hyaluronate , 2016, Journal of drug targeting.

[2]  S. Choi,et al.  Hyaluronic acid microneedle patch for the improvement of crow's feet wrinkles , 2017, Dermatologic therapy.

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

[4]  Hansen Luan,et al.  Rapidly Dissolvable Microneedle Patches for Transdermal Delivery of Exenatide , 2014, Pharmaceutical Research.

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

[6]  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.

[7]  J. Bos,et al.  The 500 Dalton rule for the skin penetration of chemical compounds and drugs , 2000, Experimental dermatology.

[8]  M. Ameri,et al.  Effect of irradiation on parathyroid hormone PTH(1-34) coated on a novel transdermal microprojection delivery system to produce a sterile product--adhesive compatibility. , 2010, Journal of pharmaceutical sciences.

[9]  H. Wulf,et al.  Epidermal thickness at different body sites: relationship to age, gender, pigmentation, blood content, skin type and smoking habits. , 2003, Acta dermato-venereologica.

[10]  J. Matriano,et al.  Parathyroid Hormone (1-34)-Coated Microneedle Patch System: Clinical Pharmacokinetics and Pharmacodynamics for Treatment of Osteoporosis , 2010, Pharmaceutical Research.

[11]  J. Bilezikian,et al.  Catabolic and anabolic actions of parathyroid hormone on the skeleton , 2011, Journal of endocrinological investigation.

[12]  Mark R Prausnitz,et al.  Microneedle patches for vaccination in developing countries. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

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

[14]  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.

[15]  K. Sugibayashi,et al.  Prediction of Skin Permeability of Drugs: Comparison of Human and Hairless Rat Skin , 1992, The Journal of pharmacy and pharmacology.

[16]  T. Sone,et al.  24-Month Open-Label Teriparatide Once-Weekly Efficacy Research Trial Examining Bone Mineral Density in Subjects with Primary Osteoporosis and High Fracture Risk , 2017, Advances in Therapy.

[17]  Suyong Kim,et al.  Physicochemical study of ascorbic acid 2-glucoside loaded hyaluronic acid dissolving microneedles irradiated by electron beam and gamma ray. , 2018, Carbohydrate polymers.

[18]  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.

[19]  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.

[20]  A. Banga,et al.  Low frequency sonophoresis mediated transdermal and intradermal delivery of ketoprofen. , 2012, International journal of pharmaceutics.

[21]  Maelíosa T. C. McCrudden,et al.  Transdermal delivery of gentamicin using dissolving microneedle arrays for potential treatment of neonatal sepsis , 2017, Journal of controlled release : official journal of the Controlled Release Society.

[22]  Peter M. Schlag,et al.  Novel Jet-Injection Technology for Nonviral Intratumoral Gene Transfer in Patients with Melanoma and Breast Cancer , 2008, Clinical Cancer Research.

[23]  A. Ardizzoni,et al.  Influence of hyaluronic acid on bacterial and fungal species, including clinically relevant opportunistic pathogens , 2011, Journal of materials science. Materials in medicine.

[24]  H. Katsumi,et al.  Trypsin as a novel potential absorption enhancer for improving the transdermal delivery of macromolecules. , 2009, The Journal of pharmacy and pharmacology.

[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]  Ryan F Donnelly,et al.  Effects of microneedle length, density, insertion time and multiple applications on human skin barrier function: assessments by transepidermal water loss. , 2010, Toxicology in vitro : an international journal published in association with BIBRA.

[27]  Eneko Larrañeta,et al.  Synthesis and characterization of hyaluronic acid hydrogels crosslinked using a solvent-free process for potential biomedical applications , 2018, Carbohydrate polymers.

[28]  Yuqin Qiu,et al.  Enhanced delivery of hydrophilic peptides in vitro by transdermal microneedle pretreatment , 2014, Acta pharmaceutica Sinica. B.

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

[30]  Akira Yamamoto,et al.  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. , 2014, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[31]  P. V. Subramanyam,et al.  ON MICRONEEDLES : AN EMERGING TRANSDERMAL DRUG DELIVERY SYSTEM , 2022 .

[32]  Ryan F Donnelly,et al.  Dissolving polymeric microneedle arrays for electrically assisted transdermal drug delivery. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[33]  R. Turner,et al.  Printed in U.S.A. Copyright © 1997 by The Endocrine Society The Effects of Programmed Administration of Human Parathyroid Hormone Fragment (1–34) on Bone Histomorphometry and Serum Chemistry in Rats* , 2022 .

[34]  Akira Yamamoto,et al.  Improvement of Transdermal Delivery of Exendin-4 Using Novel Tip-Loaded Microneedle Arrays Fabricated from Hyaluronic Acid. , 2016, Molecular pharmaceutics.

[35]  Akira Yamamoto,et al.  Efficient Transdermal Delivery of Alendronate, a Nitrogen-Containing Bisphosphonate, Using Tip-Loaded Self-Dissolving Microneedle Arrays for the Treatment of Osteoporosis , 2017, Pharmaceutics.

[36]  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.

[37]  Kiyoshi Yamaoka,et al.  Statistical moments in pharmacokinetics , 1978, Journal of Pharmacokinetics and Biopharmaceutics.

[38]  Damijan Miklavčič,et al.  Skin electroporation for transdermal drug delivery: the influence of the order of different square wave electric pulses. , 2013, International journal of pharmaceutics.

[39]  Y. Matsumoto,et al.  Prevention of bone loss in ovariectomized rats by pulsatile transdermal iontophoretic administration of human PTH(1-34). , 2002, Journal of pharmaceutical sciences.

[40]  Mahmoud Ameri,et al.  Demonstrated Solid-State Stability of Parathyroid Hormone PTH(1–34) Coated on a Novel Transdermal Microprojection Delivery System , 2009, Pharmaceutical Research.

[41]  H. Katsumi,et al.  Improvement of transdermal delivery of sumatriptan succinate using a novel self-dissolving microneedle array fabricated from sodium hyaluronate in rats. , 2015, Biological & pharmaceutical bulletin.