Bioadhesive
`Drug Delivery
`Systems
`
`Editors
`
`Vincent Lenaerts, Ph.D.
`Professor
`
`Faculty of Pharmacy
`University of Montreal
`Montreal, Quebec, Canada
`
`Robert Gurny, Ph.D.
`Professor
`
`School of Pharmacy
`University of Geneva
`Geneva, Switzerland
`
`MM
`
`CRC Press, Inc.
`Boca Raton, Florida
`
`
`
`DRL - EXHIBIT 1029
`
`DRL001
`
`DRL - EXHIBIT 1029
`DRL001
`
`

`
`
`
`Library of Congress Cataloging-in Publication Data
`
`Bioadhesive drug delivery systems / editors, Vincent Lenaerts, Robert
`Gumy
`p. cm.
`Includes bibliographies and index.
`ISBN 0-8493-5367-X
`1. Bioadhesive drug delivery systems. I. Lenaerts, Vincent.
`H. Gumy, Robert.
`[DNLM: 1. Dosage Forms. 2. Drug Administration Routes. QV 785
`B6114]
`RS201 .B54B56 1990
`615.5’_8—dc20
`DNLM/DLC
`for Library of Congress
`
`89-7256
`CIP
`
`This book represents information obtained from authentic and highly regarded sources. Reprinted material is
`quoted with permission, and sources are indicated. A wide variety of references are listed. Every reasonable effort
`has been made to give reliable data and information, but the author and the publisher cannot assume responsibility
`for the validity of all materials or for the consequences of their use.
`
`All rights reserved. This book, or any parts thereof, may not be reproduced in any fonn without written consent
`from the publisher.
`
`Direct all inquiries to CRC Press, Inc., 2000 Corporate Blvd., N.W., Boca Raton, Florida, 33431.
`
`© 1990 by CRC Press, Inc.
`
`International Standard Book Number 0-8493-5367-X
`
`Library of Congress Card Number 89-7256
`Printed in the United States
`
`
`
`DRL - EXHIBIT 1029
`
`DRL002
`
`DRL - EXHIBIT 1029
`DRL002
`
`

`
`i
`
`
`
`7KLV PDWHULDO PD\ EH SURWHFWHG E\ &RS\ULJKW ODZ 7LWOH  86 &RGH

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`105
`
`Chapter 6
`
`MUCOADHESIVE BUCCAL PATCHES FOR PEPTIDE DELIVERY
`
`Hans P. Merkle, Reinhold Anders, and Aloys Wermerskirchen
`
`TABLE OF CONTENTS
`
`I.
`
`Introduction .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. . .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. . .
`
`. .
`
`.
`
`.
`
`. . . . .
`
`. .
`
`.
`
`.
`
`. . . .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. . .
`
`.
`
`.
`
`. .
`
`.
`
`.
`
`. .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. .. 106
`
`I
`
`I
`
`‘
`
`1
`
`II.
`
`III.
`
`Relevant Anatomy and Physiology of the Oral Mucosa .
`
`. . .
`
`.
`
`. .
`
`.
`
`.
`
`.
`
`.
`
`. . .
`
`.
`
`.
`
`Dosage Form Design for Oral Mucosal Application .
`A.
`Conventional Dosage Forms .
`.
`.
`. . .
`. .
`.
`.
`. .
`.
`.
`.
`.
`.
`.
`B.
`Adhesive Dosage Forms . .
`.
`.
`. .
`.
`.
`. . . . .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`1.
`Adhesive Polymers .
`. .
`.
`.
`. . .
`.
`.
`.
`.
`.
`.
`. . . . .
`2.
`Adhesive Tablets .
`. .
`. . . . . . .
`. .
`.
`.
`. .
`.
`.
`.
`.
`.
`.
`3.
`Adhesive Gels .
`. .
`. .
`.
`.
`.
`.
`. . .
`. .
`.
`.
`. .
`.
`.
`.
`.
`.
`.
`4.
`Adhesive Patches . .
`.
`.
`.
`.
`. . .
`. .
`.
`.
`. .
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`. . .
`. . .
`
`. . .
`.
`.
`.
`. . .
`. . .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`. . .
`.
`.
`.
`.
`. .
`.
`.
`.
`. . . . .
`.
`.
`.
`.
`.
`.
`.
`.
`. . . . .
`.
`. . .
`.
`.
`.
`. . . . .
`.
`.
`. .
`.
`.
`. . . . . . .
`.
`.
`.
`.
`.
`.
`.
`. . . . .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`. . .
`.
`.
`.
`
`IV.
`
`.
`In Viva Adhesion and Release of Adhesive Hydrocolloid Patches . .
`A.
`Materials and Patch Preparations .
`. . .
`.
`.
`.
`.
`.
`.
`. . .
`.
`.
`.
`. . .
`.
`. .
`.
`.
`.
`.
`. . .
`1.
`Materials .
`.
`.
`.
`.
`.
`.
`. .
`. . .
`.
`. . . . .
`. .
`.
`.
`. .
`.
`.
`.
`.
`.
`.
`. . .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`B.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`.
`. . .
`
`.
`.
`
`. . .
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`
`.
`.
`
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. .. 107
`
`. . . .. 109
`.
`.
`.
`. . .
`. .. 109
`.
`.
`. . . . . .. 109
`.
`.
`.
`. . . .. 109
`.
`.
`. . .
`. .. 109
`.
`.
`. . .
`. .. 109
`.
`. . . . .
`. .. 110
`
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`. .. 112
`. .. 112
`.
`.
`. 112
`
`. .. 113
`.
`.
`. . . .. 113
`
`.
`.
`.
`.
`. . .
`.
`Preparation of Adhesive Patches .
`2.
`Mucosal Adhesion of Adhesive Patches In Viva .
`
`1.
`2.
`3.
`
`. .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`. . .
`.
`.
`.
`.
`. . . . .
`Experimental Procedure .
`General Observations with Adhesive Patches . .
`Duration of Mucosal Adhesion .
`.
`.
`.
`.
`.
`.
`.
`.
`. . .
`.
`.
`.
`. .
`
`. . .
`.
`.
`.
`. . .
`
`.
`.
`.
`
`. .
`.
`.
`.
`. . . . .
`.
`.
`.
`. .
`
`C.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`. . .
`. . .
`
`.
`.
`.
`
`.
`.
`.
`
`. .. 113
`.
`.
`. . . .. 113
`.
`.
`. .. 114
`
`.
`.
`.
`
`.
`.
`.
`
`. .. 116
`. .. 116
`. .. 116
`
`c.
`
`Correlation of Polymer Dissolution and Drug
`Release .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`. . .
`.
`.
`.
`.
`.
`.
`. . .
`.
`.
`.
`.
`.
`.
`. . .
`. .
`.
`.
`
`.
`
`.
`
`. . .
`
`V.
`
`.
`
`.
`
`. . .
`
`.
`
`.
`
`.
`
`. .
`.
`In Viva Drug and Polymer Release from Adhesive Patches .
`. .
`.
`1.
`Experimental Technique . .
`. . .
`.
`.
`.
`.
`. . . . . . .
`.
`. . .
`.
`. .
`.
`.
`.
`.
`.
`.
`. .
`.
`2.
`In Viva Drug Release .
`.
`.
`. .
`. . .
`.
`.
`.
`.
`. . .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`. .
`.
`.
`.
`.
`.
`.
`a.
`Effects of Polymer, Viscosity Grade of Polymer,
`and Polymer Load on In Viva Release .
`.
`.
`. . .
`.
`.
`.
`.
`.
`Between-Subject Variations of In Viva Drug
`Release .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`. . .
`.
`.
`. . .
`.
`.
`.
`.
`.
`.
`.
`. . .
`.
`.
`.
`. .
`.
`. .
`.
`.
`
`b.
`
`.
`
`.
`
`.
`
`. . .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. . .
`
`. .. 116
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. . . 1 17
`
`.
`
`. . 1 18
`
`. ..118
`
`I
`
`VI.
`
`In Vitra Adhesion Techniques . .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. . .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`.
`In Vitra Adhesion of Adhesive Hydrocolloid Patches .
`A.
`Materials and Patch Preparation .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`. . .
`B.
`In Vitro Adhesive Stress Measurement .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`1.
`Adhesion Test .
`. .
`.
`. .
`.
`.
`.
`.
`. .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`. . .
`.
`.
`.
`2.
`Adhesion Profiles .
`.
`.
`.
`.
`.
`. . .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`a.
`HEC .
`.
`.
`.
`. .
`. . .
`.
`. . .
`. .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`. . .
`.
`.
`.
`. . .
`.
`.
`.
`. . .
`.
`.
`.
`. . .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`. . .
`
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`
`.
`.
`.
`. . . . .
`.
`.
`.
`. . . . .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`. . . . .
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`. . .
`.
`.
`.
`.
`.
`.
`
`. ..121
`. . .
`. .. 122
`.
`.
`.
`.
`. . . ..122
`.
`.
`.
`. .. 122
`.
`. . . .. 122
`.
`. . . .. 122
`
`3.
`
`. . .
`Other Polymers: HPC, PVA, and PVP .
`b.
`Mechanistic View of Adhesion Test .
`.
`.
`. . .
`. .
`.
`. . .
`. .
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`. .
`. .
`
`. . .
`. . .
`
`. .. 125
`. .. 127
`
`a.
`
`b.
`
`Dynamic Stress Relaxation of Adhesive
`. .
`. . . . .
`.
`.
`. .
`Polymers .
`. . .
`.
`.
`.
`.
`.
`.
`. .
`. . . . . .
`.
`.
`.
`.
`.
`.
`.
`. .
`.
`. . .
`Static Stress Relaxation of Adhesive Polymers .
`. . .
`
`
`. 127
`.
`.
`.
`. . .
`.
`.
`. . . .. 130
`
`
`
`DRL - EXHIBIT 1029
`
`DRL003
`
`DRL - EXHIBIT 1029
`DRL003
`
`

`
`106
`
`Bioadhesive Drug Delivery Systems
`
`C.
`
`D.
`
`E.
`
`In Vitro Adhesion to Porcine Colon Mucosa .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`Evaluation of Polymers for Maximum Adhesion Capacity . .
`1.
`Effect of Polymer . .
`.
`. .
`.
`. . .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`. . .
`.
`.
`.
`. . .
`.
`.
`2.
`Effect of Polymer Load .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`. . .
`. . .
`. .
`3.
`Effect of Viscosity Grade of Polymer .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Comparison of In Vivo and In Vitro Adhesion Data . .
`.
`.
`.
`.
`. .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`.
`.
`.
`.
`
`.
`
`.
`
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`. .
`
`.
`
`.
`.
`.
`.
`.
`
`.
`
`.
`
`.
`
`.
`
`. .
`
`.
`.
`. . .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`. .
`.
`.
`.
`. . . . .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`.
`.
`.
`.
`
`.
`
`. .. 131
`
`. .. 132
`. .. 132
`. .. 132
`.
`.
`. 133
`. .. 133
`
`. .. 134
`
`References .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. . .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. . . . .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`. . .
`
`.
`
`.
`
`I. INTRODUCTION
`
`Due to an increasing supply of potent peptide and protein drugs, the biophamiaceutical
`sciences are presently faced with an urgent need to develop alternative dosage forms for
`nonparenteral absorption. Among the nonparenteral sites suitable for administering peptides
`and proteins are the mucosae of the nasal, buccal, vaginal, rectal, and even ocular routes.
`The currently most popular site is the nasal pathway. According to various reports, e.g.,
`reviewed by Su and Campanale‘ and Su et al.,’ it represents the route of choice, mainly
`because of its superior permeability to peptides as compared to the other mucosal sites.
`However, the nasal site does have distinct limitations. Upon long-term treatment, there
`might be a risk for pathologic changes of the nasal mucosa? the drug or a preservative added
`to the preparation might interfere with the ciliary activity of the membrane, as shown by
`Van de Donk and co—workers.3 Moreover, there is a debate on the consequences of vast
`individual variations in mucus secretion and turnover on the extent and rate of nasal ab-
`
`sorption; in addition, proteases and peptidases present in the mucus or associated with the
`nasal membrane may act as a dense enzymatic barrier to peptide absorption.“ It may thus
`be concluded that in spite of many promising aspects the nasal route may have its short-
`comings and not be the only answer to peptide absorption problems.
`Information on the buccal absorption of peptides is still rather scarce, except for a broad
`body of knowledge on the buccal absorption of oxytocin, e.g., by Wespi and Rehsteinerf
`Bergsjo and Jenssen,7 and Sjostedt,“ dating back to the 1960s. Moreover, for many con-
`ventional drugs, the oral mucosa has been an established absorption site. Recently more
`peptides were investigated, and it was shown that the buccal mucosa might provide a useful
`absorption site, mainly restricted to small peptides.9"“ Data are also available for vasopressin
`analogs and insulin. 15'” However, as compared to other alternative peptide absorption sites,
`such as the rectal, nasal, and vaginal mucosa, much less information is available for the
`oral mucosa.
`
`In terms of permeability, in addition to the nasal mucosa, even the rectal and the vaginal
`mucosae seem to be preferable to the buccal site. On the other hand, what makes the oral
`mucosa, mainly the buccal, the labial, and the sublingual sites rather attractive for peptide
`delivery is the combination of several aspects:
`
`-
`-
`-
`
`Excellent accessibility
`High patient acceptance and compliance
`Significant robustness of mucosa
`
`Because of the excellent accessibility of the oral mucosa, appropriate dosage forms can
`
`
`DRL - EXHIBIT 1029
`
`DRL004
`
`DRL - EXHIBIT 1029
`DRL004
`
`

`
`107
`
`be easily attached and removed at any time, if necessary. Moreover, application is usually
`painless and without significant discomfort whatsoever. Since patients are well adapted to
`the oral administration of drugs in general, the acceptance of buccal or sublingual dosage
`forms should be good, and there should be a high compliance as well. According to its
`natural function, the oral mucosa is routinely exposed to a multitude of different foreign
`compounds and, therefore,
`is supposed to be rather robust and less prone to irreversible
`irritation or damage by the drug, the dosage form, or the additives, e. g., absorption pro-
`motors, used therein. In addition, there is no sex—specificity involved as with the vaginal
`absorption. Moreover, nasal and vaginal secretions and mucus flow are subject to rather
`pronounced variations, both in qualitative as well as quantitative terms. On the other hand,
`with respect to proteolytic enzymes present in the mucosal membrane or fluid there is no
`principal difference or advantage of the oral mucosa in comparison to the other sites.
`the
`Therefore, in spite of the undoubtedly higher natural permeability of the rectal,
`vaginal, and especially the nasal mucosa, the buccal route appears to be a rather attractive
`one, but appropriate dosage forms have to be provided, and efficient absorption promotors
`should be found to increase its permeability.
`
`II. RELEVANT ANATOMY AND PHYSIOLOGY OF THE ORAL
`MUCOSA
`
`The oral cavity is lined by a relatively thick, dense, and multilayered mucous membrane
`of a highly-vascularized nature. Drug penetrating into the membrane can find access to the
`systemic circulation via nets of capillaries and arteries. The arterial flow is supplied by
`branches of the external carotid artery. The venous backflow goes via capillaries and a
`venous net is finally taken up by the jugular veins. The equally well developed lymphatic
`drainage runs more or less parallel to the venous vascularization and ends up in the jugular
`ducts.
`
`As compared to the relatively thin nasal mucosa with only a few cell layers to be
`penetrated before uptake by the systemic circulation takes place, the oral mucosa with its
`multilayered structure appears to be much more resistant against penetration of drugs.
`The epithelium of the oral cavity is in principle similar to that of the skin, with interesting
`differences regarding keratinization and the protective and lubricant mucus spread across its
`surface. The total area is about 100 cm.‘-"3 The buccal part with about one third of the total
`surface is lined with an epithelium of about 0.5 mm thickness, and the rest by one of 0.25
`mm thickness.” The multilayered structure of the oral mucosa is formed by cell divisions,
`which occur mainly in the basal layer. As reviewed by Jarrett,” the mucosa of the oral
`cavity can be divided into three functional zones. First, the mucus—secreting regions (con-
`sisting of the soft palate, the floor of the mouth, the under-surface of the tongue, and the
`labial and buccal mucosa) have a normally nonkeratinized epithelium. These regions are
`supposed to represent the major absorption sites in the oral cavity. Second, the hard palate
`and the gingiva are the regions of the masticatory mucosa and have a normally keratinized
`epidermis. Third, specialized zones are the borders of the lips and the dorsal surface of the
`tongue with its highly selective keratinization.
`An important feature of the oral mucosa as a mucous membrane is the turnover of the
`cells, which is definitely greater — ranging from 3 up to 8 days for a complete turnover —
`than that of the skin epidermis (ca. 30 days). This is because of the constant replacement
`of the nonkeratinized or partly keratinized cells, which is necessary to stabilize function and
`integrity of the mucosa. A reduction of the mucosal mitotic activity would result in a loss
`of epithelial continuity.“
`Keratinization and average size of the epithelial cells seem to have an inverse relationship.
`The mean cross-sectional area of the cells of the cheek is about 263 umz, while it is about
`
`
`
`
`
`DRL - EXHIBIT 1029
`
`DRL005
`
`DRL - EXHIBIT 1029
`DRL005
`
`

`
`108
`
`Bioadhesive Drug Delivery Systems
`
`133 p.rn2 for the cells of the keratinized palate. The basal cells of the hard palate are not
`markedly different from the basal cells producing the nonkeratinized buccal epithelium. But
`as the cells move towards the surface, increasing differences become apparent: palatal cells
`show a greater concentration of fibrillar and keratohyalin granular structures, while the
`buccal mucosa shows more glycogen granules and numerous ribosomes.”
`Another important feature of the buccal membrane is the presence of numerous elastic
`fibers in the dermis, which provide its typical elastic and robust behavior. These fibers
`represent another effective barrier against the diffusion of drug molecules into the circulation
`system.
`V
`The nature of the junction between epidennis and dermis is different in the region of
`the hard palate from that in the region of the buccal and labial mucosa. Whereas the hard
`palate is a acanthotic—type epidermis with a large contact area between dermis and epidermis,
`the buccal mucosa has a much flatter dermo—epidermal junction and, therefore, a much
`smaller contact area. The collagen fibers of the buccal mucosa are relatively unpolymerized
`and less dense as compared to those of the hard palate dermis.
`The surface of the mucous membrane is constantly washed by a stream of about 0.5 up
`to 2 1 saliva daily, produced by the salivary glands. The main glands are the three pairs of
`the parotid, the submaxillary, and the sublingual glands. The first are located under and in
`front of each ear, with ducts opening to the inner surface of the cheek. The submaxillary
`glands lie below the lower jaw releasing saliva through one duct on each side. Finally, the
`sublingual glands are located below the tongue with its ducts opening to the floor of the
`mouth under the tongue. In addition to these main glands, there is a variety of small glands
`dispersed on the tongue and the buccal and sublingual mucosa. Minor salivary glands are
`situated in the buccal, palatal, and retromolar regions of the oral cavity. There are major
`differences with respect to the type of mucins, mucin content, and secretion.
`The surface of the oral cavity is the site of a complex microbial flora. Its composition
`is widely different depending on the local type of surface. Large differences exist between
`the surface of the teeth, the gingiva, the tongue, and the buccal mucosa, etc. In order to
`retain health and appearance of the mucosae, each local bacterial composition has to be
`preserved in its balanced equilibrium containing a variety of site—speciflc species.
`Transport of drugs through the oral mucosa is most likely to occur mainly through the‘
`nonkeratinized sections. The first efficient barrier against penetration, however, is the mucin
`layer covering the oral epithelium. It consists of glycoproteins produced by the nonkeratinized
`oral mucosae, According to the moist environment, all epithelial cells are fully hydrated
`offering a maximum of permeability. Two transport routes seem to operate: i.e., (1) by
`crossing the cell membranes and (2) by using the intercellular space. The latter is supposed
`to form the ordinary passage for ions and very small molecules.”-2‘ The main route for
`regular drug molecules is by partitioning into the lipid bilayer of the cells and from there
`into the cells, etc. Hydrophilic medium and large molecules such as peptides, however, are
`not likely to cross the lipid bilayers of the cells to a great extent. Nevertheless, passage
`might occur through more polar fenestrations in the lipid bilayer. It still remains an open
`question how the junctions between the cells can be sufficiently opened to allow ready
`absorption of larger molecules. There is some evidence”-"'23 that even large molecules may
`penetrate the oral mucosa to some extent.
`A yet widely unknown influence on peptide absorption may be played by peptidase
`activity located in the saliva and the mucus layer, which is produced by the mucus secretions
`of the salivary glands, the mucosal surface, and the microbial flora. Peptidase activity is
`also supposed to be present in and between the cells and may affect peptide penetration
`through the mucosa. Further research on absorption promotors will, therefore, have to look
`into peptidase activity inhibition in the oral mucosa as a possible tool to enhance peptide
`absorption.“
`
`
`DRL - EXHIBIT 1029
`
`DRL006
`
`DRL - EXHIBIT 1029
`DRL006
`
`

`
`109
`
`III. DOSAGE FORM DESIGN FOR ORAL MUCOSAL
`APPLICATION
`
`A. CONVENTIONAL DOSAGE FORMS
`
`Delivery of a peptide drug to the oral mucosa by conventional means is limited to
`solutions or conventional buccal or sublingual
`tablets and capsules. Solutions in small
`quantities (less than about 1 ml) may be filled into capsules with the liquid being released
`upon chewing. More common dosage fonns are erodible buccal or sublingual tablets or
`capsules, respectively. Their manufacture is based on well—known techniques using appro-
`priate excipients and binders.
`Due to (1) involuntary swallowing of the dosage form itself or parts of it, and due to
`(2) the continuous salivary dilution of the suspended or dissolved drug after disintegration
`of the dosage form, there is a high risk that a major part of the drug of such dosage forms
`may not be available for absorption. Moreover, administration of conventional buccal and
`sublingual tablets and capsules does not allow drinking and eating and is, at least, a handicap
`for speaking, so any administration is restricted to rather limited periods of time and controlled
`release is not within the scope of such formulations.
`’
`
`B. ADHESIVE DOSAGE FORMS
`
`1. Adhesive Polymers
`The use of adhesive polymers plays a dominant role in the development of adhesive
`mucosal dosage forms. Close attachment of a dosage form to the buccal, sublingual, or
`gingival mucosa will retain the dosage form in the oral cavity and will establish an intimate
`contact with the absorption site. Relevant dosage forms are adhesive tablets, adhesive gels,
`and adhesive patches, which will be covered in detail below. Table 1 gives an overview on
`some of the polymers useful for this purpose.9'”’”'25‘37
`Adhesion between polymer and mucosa is established by the thermodynamics and ki-
`netics of the interaction and the intercalation of the polymer chains and the glycoprotein
`coat of the mucosa. Depending on the functional groups of both components, chemical as
`well as physical interactions may take place. A comprehensive review on the nature of
`mucosal
`interactions with polymers,
`its mechanisms, experimental methods to evaluate
`adhesion, and a survey of adhesive polymers is given by Peppas and Buri.” Fundamental
`aspects of adhesion to mucus glycoproteins are outlined by Park and Robinson.“ Basic
`information on adhesion is presented by Manly” and by Anderson et al.39
`
`2. Adhesive Tablets
`
`Adhesive tablets for buccal or sublingual administration were suggested, for instance,
`on the basis of eroding hydrocolloid/filler tablets. An example is given by Davis et al.“°
`and Schor et al.“ Hydroxypropyl cellulose (Synchron®) and lactose as excipients were mixed
`with the drug, and the mix was compressed to tablets. As shown by a scintigraphic marker
`technique, the preparation remained in place for about 3 h. This was due to the adhesion
`of the gradually eroding polymer to the buccal mucosa. Er ‘*2 evaluated adhesive buccal
`nitroglycerin tablets, as before on the basis of hydroxypropyl cellulose, and found phar—
`macodynamic effects for up to 5 h. In principle, a multitude of other polymers also seems
`to be useful for this purpose. A small portion of the patent literature was reviewed by Chien,"'3
`and a thorough review on bioadhesive polymers was given by Peppas and Bud.” Unlike
`conventional tablets, adhesive tablets allow drinking and speaking without major discomfort.
`
`3. Adhesive Gels
`
`Viscous adhesive gels as an oral mucosal dosage form may be used to deliver drugs to
`the buccal, sublingual, or gingival mucosa. Examples for local therapy have been given by
`
`
`
`
`
`DRL - EXHIBIT 1029
`
`DRL007
`
`DRL - EXHIBIT 1029
`DRL007
`
`

`
`110
`
`Bioadhesive Drug Delivery Systems
`
`TABLE 1
`
`Mucosal Adhesive Polymers
`
`Mucosal adhesive polymer
`
`Ref.
`
`Hydroxypropycellulose
`Combination of hydmxy propylcellulose and
`polyacrylic acid
`
`Polyacrylic acid
`Polymethylmethacrylate
`
`Na carboxymethylcellulose
`Methylcellulose, methylhydroxyethylcellu-
`lose, hydroxyethylcellulose, hydroxypropyl
`cellulose, polyvinylpyrrolidone, polyvinyl-
`alcohol, agarose
`Combination of hydroxy propyl cellulose
`a.nd polyacrylic acid, or polyethylenglycol,
`review
`Insoluble cross—linl(ed polyacrylic. acid poly-
`mers (polycarbophil type polymers),
`review
`Review on potentially bioadhesive polymers
`of all above mentioned classes and others
`
`25
`26
`17
`27
`28
`29
`30
`31
`32
`9, 13 ,33 ,34
`
`35
`
`36
`
`37
`
`Ishida et al.27-"’‘‘‘‘ and by Bremecker and co-workers,”'“ using polyacrylic acid and poly-
`methylmethacrylate, respectively, as gel—forming polymers. Systemic therapy with peptides
`has not yet been reported, but appears feasible. As compared to solutions, gels can signif-
`icantly prolong residence on the oral mucosa that may improve absorption and/or allow for
`some degree of sustained release of the active principle.
`
`4. Adhesive Patches
`
`Adhesive patches pose a relatively new technology to pharmacy. Design and manufacture
`may be partly derived from polymer technologies. The formulation of adhesive patches may
`take a number of different approaches: a collection of four different setups is given in Figure
`1. It shows that such patches may range from simple adhesive disks to laminated sys-
`tems.‘3*‘7"7’33'3“-45“‘7 The adhesive polymer may work as the drug carrier itself (Case a and
`d); on the other hand, it may act as an adhesive link between a drug loaded layer and the
`mucosa (Case c). Also a drug-containing disk may be fixed to the mucosa by using an
`adhesive shield (Case b). The polymers used as adhesives are in principle the same as for
`adhesive tablets and gels, with the principal types given in Table 1.
`An important difference may be seen with respect to the directions open for drug release.
`Cases a and c allow for a bidirectional release of the drug, i.e., the drug is not only delivered
`to the mucosa, but also to the oral cavity, or the saliva, respectively. This may lead, however,
`as we have seen, to a substantial loss of the drug due to involuntary swallowing of saliva.
`On the other hand, the total surface of the oral cavity is now available for absorption. Drug
`loss to the saliva may be decreased by using an adhesive protective shield (Case b) or a
`nonpermeable backing layer (Case d); however, the main absorption site now remaining is
`the rather limited mucosal area covered by the dosage form itself. Further spreading of the
`drug across the buccal mucosa may increase the effective area for peptide absorption. This
`may happen either by squeezing—out effects upon individual jaw movements or may be due
`to a slow floating motion of the device across the mucosal surface.
`The size of such systems is variable, but the maximum size suitable for buccal admin-
`
`DRL - EXHIBIT 1029
`
`DRL008
`
`DRL - EXHIBIT 1029
`DRL008
`
`

`
`111
`
`
`
`Schematic view of four different types of adhesive patches for buccal peptide
`FIGURE 1.
`delivery. Case a: bidirectional release from adhesive patch by dissolution or diffusion. Case
`b: unidirectional release from patch embedded in adhesive shield. Case c: bidirectional release
`from laminated patch. Case d: unidirectional release from laminated patch. M, mucosa; P,
`polymer with peptide; D, drug depot; S, adhesive shield; A, adhesive layer; B, impermeable
`backing layer.”""'“-33-3"""5“’7 (From Merkle, H. P. et al.,
`in Delivery Systems for Peptide
`Drugs (NATO ASI Series A), Vol. 125, Davis, S. S., Illum, L., and Tomlinson, E., Eds.,
`Plenum Press, New York, 1986, 161. With permission.)
`
`istration will be around 10 to 15 cm2 at the most. Much more convenient and comfortable
`
`'
`are patches of about 1 to 3 cm2.
`Due to the impermeable backing layer design, there is no excessive washout of the drug
`by saliva, so a maximum drug activity gradient to the mucosa is established. The washout
`of the adhesive is also diminished, which minimizes the amount of adhesive necessary to
`ensure adhesion.
`
`Depending on the size and the shape of the systems, a number of different administration
`sites is possible. Patches near the maximum size mentioned can be administered at the central
`position of the buccal mucosa only. Ellipsoid—shaped patches seem to be most suitable for
`this size. Small patches may be attached to variable sites on the buccal, labial, sublingual,
`or gingival mucosa. The labial, sublingual, and the gingival sites require rather small patches
`with a maximum of 1 to 3 cm2. It has to be pointed out that different sites are most likely
`to result in differences in drug dissolution and drug release that might affect drug absorption.
`To improve acceptance and compliance of the patches, a moderate size and high flex-
`ibility of the patches is required. This is a prerequisite for perfect adhesion and prevention
`of any local discomfort.
`All systems may be additionally loaded with any additive needed. A major advantage
`of those systems carrying a nonperrneable protective shield or layer is that the effect of the
`additives can be restricted to the very site of application. A local microenvironment may
`thus be created between the dosage form and the mucosa, which may establish more favorable
`absorption conditions than the natural mucosal site, e.g., by adjustment of a specific pH,
`or by providing an absorption promotor, if available. Furthermore, any irritation or damage
`exerted to the mucosa by the drug or any of the dosage form excipients is restricted to a
`rather limited area and not to the complete surface of the oral mucosa as it would be the
`case without the protective shield or layer. Subsequent recoverage of reversibly damaged
`sites appears to be possible, even during long—terrn treatments, since the application site
`may be varied across the total surface available, and damaged areas will be relatively small.
`Anyway, all additives released to the oral cavity have to be rather critically evaluated, since
`the oral mucosa is the site of a vulnerable and complex bacterial rnicroflora whose com-
`position and viability is essential for its health and appearance.
`The choice of polymers for oral mucosal patches follows the lines given by Table 1. A
`variety of polymers can be used, including water-soluble and insoluble hydrocolloid polymers
`from both the ionic and nonionic type. Drug release from soluble polymers is accompanied
`by the gradual erosion—type dissolution of the polymer. Polymer dissolution and drug dif-
`fusion may, therefore, determine the overall release mechanism. Drug release from non-
`soluble hydrogels follows fickian or nonfickian diffusion kinetics.” The most common
`polymer applied is the anionic polyacrylate-type hydrogel.”
`
`
`
`
`
`DRL - EXHIBIT 1029
`
`DRL009
`
`DRL - EXHIBIT 1029
`DRL009
`
`

`
`112
`
`Bioadhesive Drug Delivery Systems
`
`TABLE 2
`
`Molecular Weights and Specific Viscosity of Water-Soluble
`Hydrocolloids
`
`Polymer
`
`Trade name
`
`Molecular
`weight‘
`
`Viscosity”
`mPa-s
`
`Hydroxyethylcellulose (HEC)
`
`Hydroxypropylcellulose (HPC)
`
`Poly(vinylpyrro1idone) (PVP)
`
`Poly(vinylalcohol) (PVA)
`
`Natrosol® 250 L
`Natrosol® 250 G
`Natrosol® 250 K
`NaIIosol® 250 M
`Nan-oso1® 250 H
`Klucel® EF (E)
`K1ucel® JF (J)
`Klucel® MF (M)
`Klucel HF (H)
`Kollidon® 17
`Kollidon® 25
`Kollidon® 30
`Kollidon® 90
`Mowiol‘7" 4-88
`Mowiol® 40-88
`MOWl0l® 4-98
`Mowiol® 56-98
`
`80,0()0
`300,000
`
`650,0()0
`900,0()0
`60,000
`
`1,000,000
`9,500
`27,000
`49,000
`1,100,000
`23,300
`114,400
`23,300
`202,400
`
`14 (2%)
`300 (2%)
`2,000 (2%)
`6,000 (2%)
`30,000 (2%)
`500 (10%)
`30 (2%)
`5,000 (2%)
`2,000 (1%)
`2 (10%)
`4 (10%)
`7 (10%)
`500 (10%)
`4 (4%)
`40 (4%)
`4 (4%)
`56 (4%)
`
`“ Mean molecular weight as given by the producer.
`“ Viscosity at a given concentration of polymer in water (in parenthesis); Brookfreld
`method for HEC and HPC (25°C), Hoppler method for PVP and PVA (20°C); data
`as provided by the producer.
`
`From Anders, R. and Merkle, H. P., Int. J. Pharm., 49, 233, 1989. With permission.
`
`Depending on the pharmacodynamics of the peptides, various buccal dosage forms of
`different release rates may be designed. In some cases, fast release of the peptide may be
`required; for other peptides, a sustained release may be desirable. To achieve sustained
`release, a number of standard strategies are at hand, e. g. , matrix diffusion control, membrane-
`controlled transport of the peptide, or polymer erosion control. In many cases, however,
`instantaneous release of the peptide may be desired, which requires rapidly eroding or highly
`permeable carriers. The maximum application time span for adhesive mucosal dosage forms
`reported is in the order of several days.“ In most cases, however, the maximum buccal
`residence time should not exceed several hours. This is due to the fact that buccal devices
`
`may possibly interfere with drinking, eating, and even talking. Longer periods appear to be
`practical for nighttime administration only. Buccal patches for treatments over several hours
`have to be perfectly formulated in order to motivate patients to comply with them. A smooth
`surface and good flexibility are prerequisites to prevent mechanical irritation or local discomfort.
`
`IV. IN V1V0 ADHESION AND RELEASE OF ADHESIVE
`HYDROCOLLOID PATCHES”
`
`A. MATERIALS AND PATCH PREPARATION
`1. Materials
`
`The following water-soluble hydrocolloid mucoadhesives were used: hydroxyethyl cel-
`lulose (HEC, Natrosol® 250, Hercules, D—Hamburg), hydroxypropyl cellulose (HPC, Klu-
`cel®, Hercules, D—Hamburg), poly(vinylpyrrolidone) (PVP, Kollidon®, BASF, D-
`Ludwigshafen) and poly(viny1alcoho1) (PVA, Mowiol®, Hoechst, D-Frankfurt). Further
`information regarding molecular weight and viscosity is given in Table 2.
`
`
`DRL - EXHIBIT 1029
`
`DRLO 10
`
`DRL - EXHIBIT 1029
`DRL010
`
`

`
`113
`
`The main backing layer used in this study was Multiphor® (sheets, from LKB, D-
`Gréifelfing). Multiphor® sheets were 168 to 176 pm thick and covered on one side with a
`thin layer of agarose grafted onto the polymer. This material is commonly used as backing
`layer for gel chromotography sheets. The material available on the market is rather stiff and
`not flexible enough to allow comfortable buccal use, so it should be regarded as a model.
`In some cases cellophane (Cellophane® 325 P10, from Kalle, D-Wiesbaden) was taken as
`backing layer. According to producer information, the thickness of the cellophane in the
`dry state was 22 um.
`Protirelin (TRH) was used as a model peptide drug. In addition, sodium salicylate was
`used as a marker compound instead of the peptide.
`
`2. Preparation of Adhesive