A Fully Integrated Microneedle-based Transdermal Drug Delivery System Niclas Roxhed MICROSYSTEM TECHNOLOGY LABORATORY SCHOOL OF ELECTRICAL ENGINEERING ROYAL INSTITUTE OF TECHNOLOGY ISBN 978-91-7178-751-4 ISSN 1653-5146 TRITA-EE 2007:046 Submitted to the School of Electrical Engineering KTH—Royal Institute of Technology, Stockholm, Sweden, in partial fulfillment of the requirements for the degree of Doctor of Philosophy Stockholm 2007 ii A Fully Integrated Microneedle-based Transdermal Drug Delivery System The left picture on the front cover shows an integrated microneedle-based drug delivery system fabricated and used for experiments by the author. An array of microneedles is located on the other side of the device. The right picture on the cover shows a magnified view of these side-opened hollow microneedles, likewise fabricated by the author. The needles are designed to penetrate skin tissue using a low insertion force. The needles are fabricated by deep reactive ion etching of silicon and the length of the needles is 400 μm. Copyright 2007 by Niclas Roxhed All rights reserved to the summary part of this thesis, including all pictures and figures. No part of this publication may be reproduced or transmitted in any form or by any means, without prior permission in writing from the copyright holder. The copyrights for the appended journal papers belong to the publishing houses of the journals concerned. The copyrights for the appended manuscripts belong to their authors. Printed by Universitetsservice US AB, Stockholm 2007. Thesis for the degree of Doctor of Philosophy at the Royal Institute of Technology, Stockholm, Sweden, 2007. ABSTRACT iii Abstract Patch-based transdermal drug delivery offers a convenient way to administer drugs without the drawbacks of standard hypodermic injections relating to issues such as patient acceptability and injection safety. However, conventional transdermal drug delivery is limited to therapeutics where the drug can diffuse across the skin barrier. By using miniaturized needles, a pathway into the human body can be established which allow transport of macromolecular drugs such as insulins or vaccines. These microneedles only penetrate the outermost skin layers, superficial enough not to reach the nerve receptors of the lower skin. Thus, microneedle insertions are perceived as painless. The thesis presents research in the field of microneedle-based drug delivery with the specific aim of investigating a microneedle-based transdermal patch concept. To enable controllable drug infusion and still maintain an unobtrusive and easy-to-use, patch-like design, the system includes a small active dispenser mechanism. The dis- penser is based on a novel thermal actuator consisting of highly expandable micro- spheres. When actuated, the microspheres expand into a liquid reservoir and, subse- quently, dispense stored liquid through outlet holes. The microneedles are fabricated in monocrystalline silicon by Deep Reactive Ion Etching. The needles are organized in arrays situated on a chip. To allow active delivery, the microneedles are hollow with the needle bore-opening located on the side of the needle. This way, the needle can have a sharp and well-defined needle tip. A sharp needle is a further requirement to achieve microneedle insertion into skin by hand. The thesis presents fabrication and evaluation of both the microneedle structure and the transdermal patch as such. Issues such as penetration reliability, liquid de- livery into the skin and microneedle packaging are discussed. The microneedle patch was also tested and studied in vivo for insulin delivery. Results show that intradermal administration with microneedles give rise to similar insulin concentration as standard subcutaneous delivery with the same dose rate. Niclas Roxhed, [email protected] Microsystem Technology Laboratory, School of Electrical Engineering KTH—Royal Institute of Technology, SE-100 44 Stockholm, Sweden iv A Fully Integrated Microneedle-based Transdermal Drug Delivery System CONTENTS v Contents Abstract iii List of papers vii 1 Objectives and Overview 1 1.1Structure.................................. 1 2 Transdermal Drug Delivery 3 2.1Introduction................................. 3 2.2 Conventional needle-based administration . 3 2.3Continuousdrugdeliveryandinfusionsystems............. 4 2.4 Traditional transdermal patches . 6 2.5 Alternative techniques for transdermal delivery . 7 2.5.1 Jetinjectors............................. 7 2.5.2 Iontophoresis............................ 8 2.5.3 Sonophoresis............................ 9 2.5.4 Chemical penetration enhancers................. 10 2.5.5 Skinablation............................ 10 2.5.6 Microneedles............................ 11 2.6Intradermaldrugdelivery......................... 11 3 Skin as a Barrier 13 3.1Skinanatomy................................ 13 3.2Mechanicalpropertiesoftheskin..................... 14 3.3Modelingtheskin............................. 15 3.3.1 Skindeformation.......................... 16 3.3.2 Skinfracture............................ 17 3.4Implicationsonmicroneedletechnology................. 18 4 Microneedles for Drug Delivery Applications 21 4.1Generalaspectsonmicroneedles..................... 21 4.1.1 Microneedle types and applications . 21 4.1.2 Microneedlesfordrugdelivery.................. 22 4.2MEMS.................................... 25 4.2.1 Generalfabricationtechniques.................. 26 4.2.2 Deepreactiveionetching..................... 26 vi A Fully Integrated Microneedle-based Transdermal Drug Delivery System 4.3Solidmicroneedlearrays.......................... 28 4.4Hollowmicroneedlearrays......................... 33 4.5Concludingremarks............................ 38 5 Microneedle-based Systems 39 5.1Vision.................................... 39 5.2Dosingsystems............................... 40 5.2.1 Passivedelivery........................... 40 5.2.2 Activedelivery........................... 41 5.3Integratedmicroneedlesystems...................... 42 6 Development of an Integrated Microneedle-based System 45 6.1Dosingandactuationunit......................... 45 6.1.1 Design................................ 45 6.1.2 Fabrication............................. 46 6.2Ultra-sharphollowmicroneedles...................... 46 6.2.1 Design................................ 46 6.2.2 Fabrication............................. 47 6.3Membrane-sealedmicroneedles...................... 50 6.3.1 Design................................ 51 6.3.2 Fabrication............................. 51 6.4Integratedmicroneedlesystem...................... 52 6.4.1 Design................................ 52 6.4.2 Fabrication............................. 52 6.5Results.................................... 53 6.5.1 Dosingunit............................. 53 6.5.2 Ultra-sharpmicroneedles..................... 53 6.5.3 Membrane-sealedmicroneedles.................. 55 6.5.4 Integratedmicroneedlesystem.................. 56 6.6Discussion.................................. 57 7 Summaries of the Appended Papers 59 8 Conclusions 61 Acknowledgements 63 References 65 Glossary 81 Paper reprints 83 LIST OF PAPERS vii List of papers The presented thesis is based on the following international reviewed journal papers: 1. A Compact, Low-cost Microliter-range Liquid Dispenser based on Expandable Microspheres N. Roxhed, S. Rydholm, B. Samel, W. van der Wijngaart, P. Griss and G. Stemme Journal of Micromechanics and Microengineering, vol. 16, pp. 2740–6, Dec. 2006. 2. AMethodforTaperedDeepReactiveIonEtchingusingaModifiedBoschPro- cess N. Roxhed,P.GrissandG.Stemme Journal of Micromechanics and Microengineering, vol. 17, pp. 1087–92, May 2007. 3. Penetration-enhanced Ultra-sharp Microneedles and Prediction on Skin Inter- action for Efficient Transdermal Drug Delivery N. Roxhed, T. C. Gasser, P. Griss, G. A. Holzapfel and G. Stemme IEEE/ASME Journal of Microelectromechanical Systems, accepted for publica- tion, tentative print, Aug. 2007. 4. Painless Drug Delivery through Microneedle-based Transdermal Patches featur- ing Active Infusion N. Roxhed,L.Nordquist,B.Samel,P.GrissandG.Stemme IEEE Transactions of Biomedical Engineering, accepted for publication, tenta- tive print, July 2007. 5. Novel Microneedle Patches for Active Insulin Delivery are Efficient in Main- taining Glycaemic Control: An Initial Comparison with Subcutaneous Admin- istration L. Nordquist, N. Roxhed,P.GrissandG.Stemme Pharmaceutical Research, vol. 24, pp. 1381–8, July 2007. 6. Membrane-sealed Hollow Microneedles and Related Administration Schemes for Transdermal Drug Delivery N. Roxhed,P.GrissandG.Stemme Submitted for journal publication. viii A Fully Integrated Microneedle-based Transdermal Drug Delivery System The contribution of Niclas Roxhed to the different publications: 1 major part of design, fabrication, experiments and writing 2 major part of design, all fabrication and experiments, major part of writing 3 major part of design, all fabrication, major part of experiments and writing 4 major part of design, all fabrication, major part of experiments and writing 5 major part of design, all fabrication, part of experiments and writing 6 major part of design, all fabrication, all experiments, major part of writing The work has also been presented at the following international reviewed conferences: 7. Low Cost Device for Precise Microliter Range Liquid Dispensing N. Roxhed, S. Rydholm, B. Samel, W. van der Wijngaart, P. Griss and G. Stemme 17th IEEE Int. Conf. on Micro Electro Mechanical Systems, Maastricht, The Netherlands, Jan. 2004, pp. 326–9.