Advances in Delivery Science and Technology

The CRS flagship book series, Advances in Delivery Science and Technology, pub-lished in partnership with Springer, will serve as a wider forum for the dissemina-tion of knowledge relating to delivery, science, technology, and innovation to the benefit of CRS members and to the general scientific community. Our aim is to deliver high-quality volumes edited by authoritarians and written by opinion leaders from around the globe.

More information about this series at http://www.springer.com/series/8875

Michael J. Rathbone • Sevda Şenel • Indiran PatherEditors

Oral Mucosal Drug Delivery and Therapy

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ISSN 2192-6204 ISSN 2192-6212 (electronic)Advances in Delivery Science and TechnologyISBN 978-1-4899-7557-7 ISBN 978-1-4899-7558-4 (eBook)DOI 10.1007/978-1-4899-7558-4

Library of Congress Control Number: 2015932505

Springer New York Heidelberg Dordrecht London© Controlled Release Society 2015This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed.The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made.

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EditorsMichael J. RathboneULTI Pharmaceuticals Ltd.HamiltonNew Zealand

Sevda ŞenelHacettepe UniversityFaculty of PharmacyAnkaraTurkey

Indiran PatherCalifornia Northstate UniversityCollege of PharmacyElk GroveCaliforniaUSA

To my mother… I am unable to express my love and gratitude in words, so let me just say thank you for sacrificing so many pre-cious moments of your own life to assure my happiness and success.

MJR

Canım anneme … Bugüne kadar bana verdiğin karşılıksız sevgi, özveri ve güvenle yaşamımı anlamlı kıldın, sonsuz sevgi ve teşekkürlerimle… SŞ

To my mother… you always gave me uncon-ditional love, devotion and trust, which made my life momentous. Thank you with my love forever… SŞ

To my mother … you are the most loving and caring person I have known, and you always had complete trust and faith in your children – thank you.

IP

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Preface

Academia and industry have expressed a high interest throughout the past three de-cades in delivering drugs to or across the oral mucosa for the purpose of achieving desired therapeutic outcomes. However, because the membranes that line the oral cavity exhibit relatively poor permeability to drugs, and due to the fact that only a limited number of drugs possess the innate physicochemical properties to allow them to inherently cross the mucosa in clinically relevant amounts, we have failed to witness a large number of oral mucosal drug delivery systems become commer-cially available. This situation has stimulated much interest in conducting research that has focused on increasing the potential drug candidate list for oral mucosal therapeutic applications. Research on the use of oral mucosal permeation enhancers and mucoadhesives has resulted in advances in our knowledge of how to modify drug permeation through the oral mucosa and delivery system retention at the site of administration.

It is the editors’ belief that the prospect of the oral cavity as a site for drug deliv-ery has yet to meet its full potential and that the oral mucosal route of administration is ideally suited to improve the delivery of several existing drugs. Such delivery systems would offer market differentiation for these drugs through improved, pain-free, patient-friendly delivery systems that, when optimized, would offer a definite therapeutic improvement over existing treatments. However, great challenges face formulators who aim to deliver drugs locally to the membranes that line the oral cavity or systemically across the oral mucosa. Such challenges require innovative solutions to create drug delivery systems that provide a convenient, patient-accept-able means to relieve clinical symptoms and include ingredients that manipulate the bioavailability of drugs across the oral mucosa or provide prolonged retention at the site of absorption. This volume examines the area of oral mucosal drug de-livery and the therapeutic opportunities for the use of the oral mucosa as a site of administration for drug delivery. It is our hope that the contents of this book will arm future researchers with the relevant information for them to develop new drug delivery systems that result in the oral mucosa becoming an important future site of administration for drug delivery.

In Chap. 1, Thomas P. Johnston reviews the most relevant aspects of oral mu-cosal and mouth anatomy and physiology and relates its relevance to local and

viii Preface

systemic oral transmucosal drug delivery. Some of the concepts addressed involve the advantages and disadvantages of oral mucosal drug delivery, the various sites of drug delivery within the mouth, factors that influence drug delivery associated with the gross and the microenvironment within the oral cavity (e.g., mucus, saliva, and salivary glands), and practical considerations regarding tissue irritation and/or dam-age when using this route of drug administration. Johnston also examines the role of permeation enhancers and buffering agents/pH modifiers in oral transmucosal drug delivery. The fundamental anatomical and physiological information provided in this chapter will build a sound background for those pharmaceutical scientists directly involved with the formulation of dosage forms intended for oral mucosal drug delivery.

In Chap. 2, Rathbone, Pather, and Şenel explore the reasons for developing oral mucosal drug delivery systems, and identify the key considerations in the design and development of oral mucosal drug delivery systems. Throughout the chapter, the authors describe the characteristics of many of the delivery systems that have been successfully developed and commercialized for use in this site for drug delivery.

The permeability of many drugs through the mucosa of the oral cavity is slow due to the inherent barrier properties of the mucosa that line the oral cavity. There-fore, the enhancement of permeation of the drug is needed to extend the drug can-didate list for this route of administration. In Chap. 3, Pather and Kolli examine the use of chemicals that promote the passage of the drug through the oral mucosa and describe the different classes of compounds that may be useful to enhance oral mucosal drug permeation. Pather and Kolli adopt a broad view of the concept of “chemical methods for enhancing delivery,” thus, effervescent agents and chemi-cals that assist in retaining the dosage form on the mucosa for an extended time, thereby allowing a longer time for drug permeation, are included in this chapter.

In Chap. 4, Sandri et al. examine the mechanism of action, functional character-istics, selection, and assessment of mucoadhesive polymers as enabling excipients for oral mucosal drug delivery. The authors identify and discuss several classes of polymers that have been proved to possess pronounced adhesion properties when placed in contact with oral mucosa. They also define the key properties that facili-tate these molecules achieving prolonged adhesion onto oral mucosa, which include their ability to spread over the mucosal surface, their swelling properties, their ionic (cationic and anionic) charge density, and their hydration and consequent mucus de-hydration properties. The chapter provides an in-depth look at the assessment of the mucoadhesive properties of the compounds and the rationale for their selection by the formulation scientist for their inclusion in an oral mucosal drug delivery system.

Authors Giannola, De Caro, and Sutera examine the physical methods for en-hancing oral mucosal delivery in Chap. 5. The authors examine the use of sonopho-resis, iontophoresis, and electroporation methods in the area of oral mucosal drug delivery and review the ability of these techniques to increase the drug flux through the oral mucosal membranes. The authors highlight that these physical methods are extensively used to enhance drug permeation through the skin but have yet to become widely used for increasing drug permeation of the membranes that line

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the oral cavity, despite the fact that they are very promising in this regard and are gaining in popularity due to their noninvasive and convenient means for local or systemic delivery of drugs.

In Chap. 6, Kolli and Pather define the methods used to characterize oral muco-sal drug delivery from the perspective of both the drug and its formulation. The au-thors highlight that even though drug delivery across the oral mucosa has emerged as a useful alternative for compounds that cannot be delivered orally, standardized methods to evaluate drug absorption across oral mucosal membranes, either in vitro or in vivo, and standardized techniques used to characterize oral mucosal drug de-livery systems have yet to be agreed upon. Their chapter provides a comprehensive review of the current in vitro and in vivo methodologies employed in the literature for evaluating oral transmucosal absorption of compounds. In addition, it reviews the use of buccal cell cultures as a means to study oral mucosal drug absorption. In the second part of their chapter, the authors examine of the methods used to test oral mucosal drug formulations including residence time, mucoadhesion and drug release.

In Chap. 7, Rathbone, Pather, and Şenel take an in-depth look at systemic con-trolled release oral mucosal drug delivery systems and the clinical opportunities that currently exist for this type of drug product. The chapter describes the potential of the oral cavity as a site for the systemic delivery of drugs alongside some of the problems and their solutions and examines the research in these areas and how they have resulted in extending the clinical opportunities for the use of the oral mucosa as a site for drug delivery.

Tablets for systemic oral mucosal drug delivery are reviewed in Chap. 8 by Rane and Moe. The chapter focuses on the formulation and performance of solid dos-age forms commonly used in oral transmucosal delivery. The authors highlight the specific challenges associated with the oral cavity as a route of drug administration together with the products used for transmucosal delivery that are more effective and sometimes safer than conventional dosage forms. They also discuss clinical studies that directly compare conventional dosage forms with oral transmucosally delivered products. The authors expertly define the basic principles of oral transmu-cosal drug delivery and explore new developments in-depth. Examples of formula-tion technologies and clinical performance from successful and widely known oral transmucosally delivered products are provided. Overall, this chapter comes to the conclusion that there is a large scope in further development of strategies for oral transmucosal drug delivery that could be applied to as yet unexplored molecules.

A relatively new area of research and application of the oral cavity is that of the formulation of delivery systems for photosensitisers that are therapeutically used in oral cavity photodynamic therapy. Photodynamic therapy is a clinical treatment that combines the effects of visible light irradiation with subsequent biochemical events that arise from the presence of a photosensitizing drug to cause destruction of selected cells. Following administration, the photosensitizer accumulates in the target cells and a measured light dose of appropriate wavelength is then used to irradiate the target tissue that activates the drug. In Chap. 9, Donnelly reviews the current status and future potential of this area to oral mucosal drug delivery. The

x Preface

chapter provides a clear message that photodynamic therapy has an important role to play in the treatment of neoplastic and dysplastic disease at body sites amenable to irradiation, and in the future this may include the oral cavity where local delivery can have a large role to play in the treatment of such local oral mucosal diseases.

In Chap. 10, Caramella et al. describe the current status of medical devices as a supportive care for oromucosal pathologies. The chapter examines the opportuni-ties offered by medical devices and provides an interesting example, even though there are currently many unmet needs in the treatment of oromucosal pathologies. The authors introduce the area that includes definitions and relevant regulations and the oral conditions that can be treated with a medical device. In addition, the mechanisms of action by which medical devices function are reviewed, and a list of products available on the market is included in the chapter. At the end of the chapter, the authors summarize their ongoing work in this area and provide a fascinating case study on a new improved class II medical device.

In the final chapter, Hughes and Ghosh provide a general overview of the U.S. Food and Drug Administration’s regulatory considerations for intraoral drug prod-uct development and marketing approval. The authors highlight that effective drug delivery through the oral mucosa is complex, and only a few products have so far achieved commercial success. They discuss the often unpredictable scientific hurdles and suggest that a good understanding of the regulatory requirements for product development is critical for maximizing resources and positive interactions with the regulatory authorities. The chapter provides an overview that will allow scientists to successfully navigate through the U.S. regulatory approval process and underscores that such an attempt will require an interdisciplinary approach from the legal, clinical, chemistry, clinical pharmacology, nonclinical and biopharmaceutics perspectives.

The editors of this volume sincerely thank the authors for their time, efforts and patience in the compilation of this volume. We are indebted to their exceptional knowledge and understanding of the area and for their willingness to put down in words and share their years of experience in this field. We have enjoyed the op-portunity to compile the book, and we hope that other scientists will benefit from reading the authoritative chapters contained within this volume.

Michael J. RathboneSevda Şenel

Indiran Pather

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Contents

1 Anatomy and Physiology of the Oral Mucosa ......................................... 1Thomas P. Johnston

2 Overview of Oral Mucosal Delivery ......................................................... 17Michael John Rathbone, Indiran Pather and Sevda Şenel

3 Chemical Methods for Enhancing Oral Mucosal Delivery .................... 31Indiran Pather and Chandra Sekhar Kolli

4 Mucoadhesive Polymers as Enabling Excipients for Oral Mucosal Drug Delivery .............................................................................. 53Giuseppina Sandri, Silvia Rossi, Franca Ferrari, Maria Cristina Bonferoni and Carla M. Caramella

5 Physical Methods for Enhancing Oral Mucosal Delivery: Sonophoresis, Iontophoresis and Electroporation .................................. 89L. I. Giannola, V. De Caro and F. M. Sutera

6 Characterization Methods for Oral Mucosal Drug Delivery ................. 125Chandra Sekhar Kolli and Indiran Pather

7 Design and Development of Systemic Oral Mucosal Drug Delivery Systems ........................................................................................ 149Michael John Rathbone, Sevda Şenel and Indiran Pather

8 Tablets and Other Solid Dosage Forms for Systemic Oral Mucosal Drug Delivery .............................................................................. 169Sagar S. Rane and Derek Moe

9 Formulation of Delivery Systems for Photosensitisers Used in Oral Cavity Photodynamic Therapy .................................................... 207Ryan F. Donnelly

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10 Medical Devices for Oral Mucosal Applications ..................................... 225Carla M. Caramella, Maria Cristina Bonferoni, Giuseppina Sandri, Eleonora Dellera, Silvia Rossi, Franca Ferrari and Fabio Macchi

11 Pharmaceuticals for Oral Mucosal Drug Delivery: Regulatory Considerations ............................................................................................ 247Minerva Hughes and Tapash Ghosh

Index .................................................................................................................. 275

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Contributors

Maria Cristina Bonferoni Department of Drug Sciences, University of Pavia, Pavia, Italy

Carla M. Caramella Department of Drug Sciences, University of Pavia, Pavia, Italy

V. De Caro Department of Biological Chemical and Pharmaceutical, Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy

Eleonora Dellera Department of Drug Sciences, University of Pavia, Pavia, Italy

Ryan F. Donnelly School of Pharmacy, Queens University Belfast, Medical Biology Centre, Belfast, UK

Franca Ferrari Department of Drug Sciences, University of Pavia, Pavia, Italy

Tapash Ghosh U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD, USA

L. I. Giannola Department of Biological Chemical and Pharmaceutical, Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy

Minerva Hughes U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD, USA

Thomas P. Johnston Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA

Chandra Sekhar Kolli College of Pharmacy, California Health Sciences University, Clovis, CA, USA

Fabio Macchi Helsinn Healthcare S.A., Lugano/Pazzallo, Switzerland

Derek Moe R&D Formulations, Cima Labs, Inc, Brooklyn Park, MN, USA

Indiran Pather College of Pharmacy, California Northstate University, Elk Grove, CA, USA

Sagar S. Rane R&D Formulations, Cima Labs, Inc, Brooklyn Park, MN, USA

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Michael John Rathbone ULTI Pharmaceuticals Ltd., Hamilton, New Zealand

Silvia Rossi Department of Drug Sciences, University of Pavia, Pavia, Italy

Giuseppina Sandri Department of Drug Sciences, University of Pavia, Pavia, Italy

Sevda Şenel Faculty of Pharmacy, Hacettepe University, Ankara, Turkey

F. M. Sutera Department of Biological Chemical and Pharmaceutical, Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy

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Biographical Sketches of Editors

Indiran Pather serves as Director of Research and Professor of Pharmaceutics at the California Northstate University College of Pharmacy (CNUCOP). After completing the B. Pharm. degree, he practiced as a pharmacist in South Africa. He subsequently completed the M. Pharm. and D. Pharm. degrees in Pharmaceutics. He taught in South Africa before joining the University of Missouri as a Research Assistant Professor. Since then, he has worked in the industry and held positions of increasing responsibility up to Director of Pharmaceutical Sciences. At CNUCOP, he teaches courses in Compounding and Biopharmaceutics and Drug Delivery. His research has involved analytical chemistry, novel drug delivery systems, and the formulation of cosmetics, pharmaceuticals, and animal health products. Prof. Pather holds 17 U.S. patents and has published 31 patent applications. He is a reviewer for several international pharmaceutical journals. His present research interests involve the formulation of novel drug delivery systems (especially oral transmucosal), find-ing new uses for established drugs, and in natural products. He currently serves as consultant to pharmaceutical companies.

Michael J. Rathbone is Founder and Managing Director of ULTI Pharmaceuti-cals, a veterinary pharmaceutical company located in New Zealand. He was for-merly Professor of Pharmaceutical Technology and Dean, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia. Prior to this, he was Associate Professor of Pharmaceutics, School of Pharmacy, Griffith University, Australia, and the Director of Research and General Manager of InterAg, where he spearheaded the companies veterinary controlled drug delivery research and direct-ed their national and global collaborative research activities. Dr. Rathbone obtained his PhD in Pharmaceutics from the University of Aston, Birmingham, UK. He is a Fellow of the Controlled Release Society and has edited eight books in the area of modified release drug delivery and 10 special theme issues of journals.

Sevda Şenel is Professor of Pharmaceutical Technology at Hacettepe University, Faculty of Pharmacy, Turkey. She is internationally recognized for her contribu-tion to the areas of mucosal drug and vaccine delivery, veterinary drug delivery and dental drug delivery. Prof. Şenel has been the recipient of many national and

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international grants and has published more than 150 communications to scientific meetings, papers in refereed journals, book chapters and books. She has served as the Editor-in Chief of the FABAD Journal of Pharmaceutical Sciences and cur-rently serves on the Editorial Boards of the Journal of Drug Delivery Science and Technology, Pharmaceutical Technology and Development, and the Polish Chitin Society Journal, Progress in the Chemistry and Application of Chitin and its Deriv-atives. She served as the President of the European Chitin Society for two terms and currently sits on several committees of the Controlled Release Society and on two advisory committees at The Drug and Medical Device Agency of Turkey. Professor Şenel has received many honors, awards, and fellowships, and most notably has been honored with the Distinguished Scientist Award by the Academy of Science of the Turkish Pharmacists Association and the Hacettepe University Science Award.