This material may be protected by copyright law (Title 17,
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`llral Mmgusal
`Ilruu Ilellverv
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`Larrv L._ Augsburger
`University of Maryland
`Baltimore, Maryland
`
`David E. Nichols
`Purdue University
`West Lafayette, Indiana
`
`Douwe D. Breimer
`Sylvius Laboratories
`Leiden. The Netherlands
`
`Stephen G. Schulman
`University of Florida
`Gainesville. Florida
`
`Trevor M. Jones
`The Association of the
`British Pharmaceutical Industry
`London. United Kingdom
`
`Jerome P. Skelly
`Copley Pharmaceutical, Inc.
`Canton, Massachusetts
`
`Hans E. Junginger
`LeidenlAmsterdam Center
`for Drug Research
`Leiden, The Netherlands
`
`Felix Theeuwes
`Alza Corporation
`Palo Alto, California
`
`Vincent H. L. Lee
`University of Southern California
`Los Angeles, California
`
`Geoffrey T. Tucker
`University of Sheffield
`Royal Hallamshire Hospital
`Sheffield, United Kingdom
`
`Peter G. Welling
`Parke-Davis. Inc.
`Ann Arbor, Michigan
`
`DRUGS AND THE PHARMACEUTICAL SCIENCES
`
`A Series of Textbooks and Monographs
`
`edited by
`
`James Swarbrick
`AA], inc.
`Wilmington, North Carolina
`
`. Pharmaco kinetics, Milo Gibeldi and Donald Perrier
`. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total
`Quality Control, Sidney H.
`I/I/illig, Murray M. Tuckerrnan, and lllfrlliam
`S. Hitchings IV
`. Microencapsulation, edited by J. R. Nixon
`. Drug Metabolism: Chemical and Biochemical Aspects, Bernard Tests
`and Peter Jenner
`
`. New Drugs: Discovery and Development, edited by Alan A. Rubin
`. Sustained and Controlled Release Drug Delivery Systems, edited by
`Joseph R. Robinson
`-
`. Modern Phannaceutics, edited by Gilbert 3. Banker and Christopher
`T. Rhodes
`
`-. Prescription Drugs
`Sch wartz
`
`in Short Supply: Case Histories, Michael A.
`
`. Activated Charcoal: Antidotal and Other Medical Uses, David 0.
`Cooney
`
`. Concepts in Drug Metabolism (in two parts), edited by Peter Jenner
`and Bernard Tests»
`
`11.
`
`12.
`
`13.
`14.
`
`15.
`
`16.
`
`17.
`
`Pharmaceutical Analysis: Modern Methods (in two parts). edited by
`James W. Munson
`
`Techniques of Solubilization of Drugs, edited by Samuel H. Yalkow-
`sky
`Orphan Drugs, edited by Fred E. Karch
`Novel Drug Delivery Systems: Fundamentals, Developmental Con-
`cepts, Biomedical Assessments, Yie W. Chien
`Phannacokinetics: Second Edition, Revised and Expanded, Milo
`Gibaldi and Donald Perrier
`
`Good Manufacturing Practices for Pharmaceuticals: A Plan for Total
`Quality Control, Second Edition, Revised and Expanded, Sidney H.
`Willig. Murray M. Tucken-nan, and William S. Hitchings IV
`Formulation of Veterinary Dosage Forms, edited by Jack Blodinger
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`Ratlabone et :1
`
`M. A. Hussain, B. J. Aungst, C. A. Koval, and E. Shefier, Improved
`buccal delivery of opioids analgesics and antagonists with bitterless
`prodrugs,Pharm. Res. 5:615 (1933).
`M. M. Veillard, M. A. Longer, T. W. Martens, and J. R. Robinson,
`Preliminary studies of oral mucosal delivery of peptide drugs, J.
`Control. Rel. 6:123 (1987).
`f 1
`d
`adh
`R. Anders, and H. P. Merkle, Evaluation 0
`aminate muco
`patches forbuccal drug delivery, Int. J. Pharm. 49:23lf(1989c)l.e dm J
`H. P. Merkle, and G. J. M. Wolany, Buccal delivery 0 pepti
`gs,
`-
`Control. Rel. 21355 (1992).
`Y. Nozaki, M. Kakumoto, M. Ohta, K. Yukimatsu, and Y. Chien, A new
`transmucosal therapeutic system: overview of formulation development
`and in vitro I in Vivo Clinical Pelfoflnflncea Drug De“ 1'14 Pham
`l9:22l (1993).
`W. J. Conine, and M. J. Pikal, Special tablets. Sublingual and buccal
`tablets, Pharmaceutical Dosage Forms. 1. Tablets. Volume I (H. A.
`Lieberman, and L. Lachman eds.), Marcel Dekker, New York, 1980, p.
`259
`M. R. Rassing, Chewing gum as a drug delivery system, Adv. Drug Del.
`Rev., 13:89 (1994).
`
`esive
`
`'
`
`_
`'
`
`_'
`
`:'
`
`.
`
`‘
`
`._
`
`.
`
`.
`
`-,
`"
`j
`I
`,
`I
`i
`LL
`
`_
`
`'
`
`_‘.
`.,
`
`1 2
`
`'
`
`'
`
`Speclallzed Oral Mucosal Drug
`'
`.
`Dehvery Systems‘ Patches
`
`Gary DeGrade, Luce Bones,
`Francoise Horriére, Herve Karsenty, Claire Lacoste
`3MSanté, France
`Roy Mcquinn Jiamflwa Gun Robert Scherrer
`’
`’
`3MPharmaceuticals, USA
`
`I.
`
`INTRODUCTION
`
`It is our view that the best illustration of what is involved in the design of oral
`mucosal (buccal) patches for the systemic delivery of drugs is our own
`experience. Our work covers the fiill range from developing new test methods
`and assessing structure-property relations through studies of drug delivery in
`animals, tests of patch positioning and comfort in human subjects, and clinical
`studies of delivery efficacy. Recent. publications on the subject have been
`incorporated into this review, but much of what is reported here has not been
`published before. Our discussion is prefaced by a summary of the principles of
`transmucosal drug delivery and the problems that must be overcome to design
`a successful product. Many of these issues are reviewed in greater detail in
`earlier chapters of this book.
`The oral cavity has a number of features that make it desirable for drug
`delivery: a rich blood supply that drains directly into the jugular vein, thus
`bypassing the liver and sparing the drug from first-pass metabolism [1, 2]; ease
`285
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`285
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`DeGrande et al
`
`Patches
`
`337
`
`of drug delivery even in unconscious patients and those who are permitted
`nothing by mouth [3]; ready termination of delivery by the healthcare
`practitioner or the patient; and an abundance of usable sites capable of
`recovering rapidly from any insult
`[3]. Therefore, despite its potential
`drawbacks - the physical and metabolic barriers to drug uptake and the
`numerous ways a drug or its delivery system can be lost [3] - many efforts
`have been made to utilize the oral surface clinically. The buccal mucosa was
`first investigated as a potential site for drug delivery several decades ago [4, 5],
`as it is an ideal surface for the placement of retentive delivery systems [2].
`
`A. Pertinent Features of the Oral Mueosa
`
`The mucosa of the mouth may be thought of as a multilayer laminate [6]. The
`outer layer is the saliva, which may take the form of an unstirred fluid layer
`[7]. Several components of the saliva may affect tranucosal delivery (TMD)
`systems. For example, the high molecular weight mucin known as MG! [7]
`may be important
`in bioadhesion. Saliva also contains several proteins,
`including some enzymes, that may bind or inactivate a dmg, reducing the
`concentration available to drive absorption [3, 8]. The pH of saliva is between
`6.5 and 7.5 [3].
`The next layer, the epithelium, may be either partly lceratinized or entirely
`nonkeratinized, the former type being less permeable to hydrophilic drugs [8].
`In the buccal region, the epithelium is nonkeratinized and approximately 500
`to 600 pm in thiclcness [9]. Chronic inflammation and physical damage to the
`epithelium may reduce its barrier function (increase the permeability) [7].
`Underlying the epithelium are a basement membrane (basal lamina) and the
`lamina propria. The latter is readily permeable to many drugs, whereas the
`former may limit the rate at which some drugs (e.g., [3 blockers) are absorbed
`[6]. The blood flowing through the vessels in the lamina propria acts as a sink
`for drugs delivered transmucosally [9].
`
`B.
`
`Pertinent Features of Drug Uptake from the Oral Mucosa
`
`Drugs applied to the oral mucosa gain apcess to the circulation principally by
`passive diffusion according to Ficlc's law [1, 3]. For the most part, drugs move
`
`I Specialized transport systems such as carrier-mediated transport or facilitated diffusion
`are operative for a small number of drugs; cefadroxil being one example [6].
`
`extracellularly and follow, not the shortest path, but the path of least resistance
`[_6|, which for most agents is through the neutral lipids and glyoolipids that
`separate the cells. The lipid solubility of a candidate drug therefore is one
`important measure of its suitability for a TMD system [6]. Also, because
`passive diffusion involves nonionized species, the pKa of a candidate drug is
`important [6, 7].
`
`C. Pertinent Considerations in the Design of a TMD System
`
`Successful transmucosal drug delivery requires at least three things: (i) a
`bioadhesive to maximize the intimacy of contact with the mucosa for a time
`sufficient for optimal drug delivery and to retain the delivery system in the oral
`cavity; (ii) a vehicle to release the drug at an appropriate rate under the
`conditions prevailing in the mouth; and (iii) strategies to overcome the low
`permeability of the oral mucosa (increase bioavailability).
`The drug selected for a TMD system must have physicochemical
`properties, including size and pKa, that will allow it to move through the
`mucosa at a rate sufficient to produce a sustained therapeutic concentration in
`the blood [1, 6, 10]. It must either resist or be protected from the various
`metabolic barriers in the form of salivary and tissue enzymes [8]. The drug and
`the other materials must not damage the teeth or oral
`tissues (e.g., by
`keratinolysis, discoloration,
`irritation, allergenicity, or alterations in the
`microflora) and they must not produce an objectionable flavor [3, 11].
`A TMD system may be unidirectional (i.e., release the drug only into the
`mucosa) or bidirectional (i.e., release drug into the mouth as well). The system
`must be of a surface area and thickness acceptable to the patient while holding
`and releasing sufficient drug for therapeutic needs. We find that flexible
`patches having a surface area of 0.5 to 1 cm1 are comfortable, although larger
`patches may be tolerated. The shape and conspicuousness of the system are
`other considerations. Lastly, the TMD system must remain in the desired
`position.
`The principal mechanism for bioadhesion of oral TMD patches appears to
`be physical entanglement of the a'dhesive polymer of the patch in the mucus
`glycoprotein chains overlying the mucosa [11]. Primary (covalent) and
`secondary (electrostatic, hydrogen, hydrophobic) chemical bonding appear to
`be less important mechanisms. The binding properties of a given polymer are
`affected by its molecular weight, configuration, cross linking density, charge
`and degree of ionization, concentration, and extent of hydration [I1]; and the
`duration of adhesion is affected by the type and amount of the adhesive
`polymer, its viscosity, and the method of patch manufacture [12].
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`288
`
`DeGrnnde et nl
`
`Patches
`
`D. Comparison of Transmueosal with Other Drug Delivery Systems
`
`I. Matrix System
`
`Although direct comparative data in humans are limited, animal models
`demonstrate that transmucosal drug delivery has unique characteristics not
`easily obtained with other methods, including rapid onset of drug delivery,
`sustained release of the drug, and rapid decline in the serum concentration of
`the drug when the TMD patch is removed. Preliminary data [13, 14] show that
`T'MD systems can provide a significantly faster initiation and decline of
`delivery than do transdermal patches. Transmucosal delivery appears to have
`low intersubject variability, particularly in comparison with oral controlled
`release formulations. Transmucosal delivery of larger molecules such as low
`molecular weight (LMW) heparin has been demonstrated. Thus, T'MD systems
`hold particular promise as an alternative for some drugs now deliverable only
`by injection.
`
`Drug and Excipients
`(in eluding
`Adhesive)
`
`Mucasal Membrane
`
`II. Reservoir System
`
`Adhesive
`
`1]. DEVELOPMENT OF A PATCH FOR TRANSMUCOSAL
`DELIVERY
`
`Drug and Excipients
`
`The TMD patch developed by 3M Pharmaceuticals has been given the name
`Cydot”. It is either a unidirectional or a bidirectional bioadhesive dosage form
`able to deliver an active drug for either systemic or local action while suffering
`little or no erosion. The thin flexible patch can be a simple matrix in which the
`drug is dispersed, a multilayer matrix with each layer having a different
`concentration of the same drug or different drugs, or a reservoir. A patch shape
`(circular, elliptical, square, or rectangular) can be chosen according to is
`intended site of placement, the surface area of the site being the predominant
`consideration. A protective backing shields the patch from saliva, reducing
`erosion and drug loss via the oral route (see Figure 1).
`The matrix patch is a mixture of elastomeric compound(s) and polymeric
`resin(s) in which the active drug is dispersed. The reservoir patch has a similar
`bioadhesive matrix containing a cavity in which various pharmaceutical
`formulations can be placed (Figure 1). Investigation of such patches has shown
`that it is possible to deliver many kinds of drugs (small and large [200 to
`10,000 Da], lipophilic and hydrophilic) at various doses (0.25 - >30 mg) to
`obtain plasma drug concentrations in the range of picograms to micrograms
`per milliliter [15]. If necessary, additives (e.g., solubilizers and penetration
`enhancers) can be incorporated. The easiest molecules to deliver are the small
`ones that are active at low plasma concentrations and have an appropriate
`partition coefllcient.
`Two primary types of manufacturing processes have been developed to
`produce the TMD system: solvent cast and direct milling (with or without
`
`Figure 1. Alternative matrix and reservoir patch designs. These extend formulation
`options and the list of potentially deliverable therapeutic agents.
`
`Mucasal Membrane]
`
`solvent). The intermediate product is a sheet fiom which patches are punched.
`A backing is then applied to each patch to control the direction of drug
`delivery and to minimize deformation and disintegration during residence in
`the mouth.
`
`Figure 2 shows three ofthe possible patch designs. The design in Panel A
`has a bafiier on the top and edge, making drug diffusion unidirectional. Panel
`B shows a patch with a semipermeable barrier that allows drug delivery. Such
`a design would be useful for delivery of drug to treat intraoral disease. The
`design in Panel C has a drug retentive barrier on the top only; as a fimction of
`the drug, this patch will deliver drug transmucosally and/or orally.
`
`III.
`
`IN VITRO TESTING
`
`It has been our experience that one can easily be misled by in vitro testing
`results and.that the value of a particular formulation/patch design must be
`verified by In vivo testing. In vitro studies are still useful, however, in that they
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`DeGrande et al
`
`Hydration Level 1.7%
`PIB = L100
`
`Unidirectional
`release
`
`Multidirectional
`release
`
`Figure 2. By varying the extent and permeability of a backing, a patch can be
`designed to provide delivery ranging from primarily systemic to predominantly local
`(oral cavity).
`
`yield a general qualitative evaluation of basic properties such as adhesion and
`drug release and provide a valuable aid for formulation optimization. Recent
`developments such as the use of diffusion cells for assessing drug permeation
`through slices of excised animal buccal tissue may create a more prominent
`role for in vitro methods of studying drug permeation and the development of
`delivery devices. The use of cultured buccal epithelium to study drug transport
`and metabolism likewise may assist in the rapid development of buccal drug
`delivery products, as discussed in Chapter 6 of this book.
`
`A. Characterization of Bioadhesion
`
`1.
`
`Initial‘ adhesion
`
`One advance that was a marked help in patch design was the finding that
`bioadhesive patches adhere to a hydrogel film comprised of a blend of
`polyvinylpyrrolidone (PVP) and cellulose acetate [16]. The extent of adhesion
`to a wet hydrogel film qualitatively parallels the experience of human subjects
`wearing the patches. The porous film allows hydration through the adhering
`side of the patch during studies of initial adhesion, duration of adhesion,
`swelling rate, -and drug release. Adhesion is measured using an Instron
`machine (Model 4201, instron Co., Canton, MA).
`
`_|. 3
`
`FeelStrength,G/CM O—l.
`
`
`
`
`
`60
`
`75
`
`Percent PAA
`
`Figure 3. Eflect of PAA concentration on force required to remove a PAAIPIB patch
`from a wet hydrogel film.
`
`As an illustration of the relative value of various bioadhesive polymers in
`the formulation of a patch, Gun [17] compared polyacrylic acid (PAA),
`hydroxypropyl methylcellulose, chitosan, and acacia in patches made with a
`combination of polyisobutylene (PIB) and polyisoprene (PIP). The PAA is
`Carbopoll“ 934P (B. F. Goodrich). The average peeling strength of samples
`made with this PAA was 0.021 kgfrnm, nearly triple the value for
`hydroxypropyl methylcellulose. This result is in agreement with that of Smart
`et al [18], who used a surface tension technique similar to the Wilhelmy plate
`method and found that PAA was the second strongest among 11 adhesive
`materials tested. These results confirmed the choice of PAA for formulating
`the patches." A study was conducted to assess the effects of the PAA
`concentration on adhesion in an experiment using the Instron adhesion test
`[19]. The maximum force tolerated without detachment (peeling strength) rose
`with the percentage of polymeric resin (Figure 3). The need for other
`ingredients to maintain patch integrity limited the upper concentration of PAA
`that could be used effectively in the formulation.
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`l)eGrande et al
`
`Patches
`
`293
`
`
`
`
`
`PeelStrength.G/CM
`
`75 Percent PAA
`
`_|. C3
`
`0
`
`R-sq = 0.955
`
`------95% Confidence Limits
`
`4
`
`initial Water in PM, %
`
`l:'.fl‘ect of prehydration of PAA on peel strength of PAAIPIB patches
`Figure 4.
`adhering to a wet hydrogel film.
`
`The effect of the initial extent of hydration of the PAA on mucoadhesion
`was determined. The PAA was prehydrated in a high humidity atmosphere to
`1.7%, 4.1%, or 8.9% water.
`It was then milled with PIB at various
`concentrations, and the resulting material was tested for bioadhesion as
`described above. The peeling strength was dramatically affected by hydration,
`correlating inversely with the water content of the polymer. The results at a
`fixed PAA content are shown in Figure 4 [19].
`
`2. Duration ofadhesion
`
`Because bioadhesive materials are affected by water and some may dissolve in
`the oral cavity, it is important to establish the duration of the adhesive force
`provided by the chosen polymer [12]. A variety of methods can be employed
`for these measurements [18, 20, 21]. We used the Instron instrument to assess
`adherence between polymer patches and the hydrated PVPlcel]ulose acetate
`hydrogel after various hydration times. Adhesion was expressed as the average
`peeling strength (kglmm) or load (kg) [17]. For tests of the duration of
`adhesion, in vitro findings were also assessed in animals and human volunteers.
`The relation of patch composition to duration of adhesion is a complex
`one, in part relating to the rate of patch hydration (Section IlI.B.). An example
`
`of an in vitro study is described by Gun [17]. Patches having PAAIPIB/PIP
`ratios of 60l3S/5 and 50/43.75/6.25 behaved similarly in that the initial
`maximum adhesion was found after 2 to 8 hours of contact with the test
`medium, with no significant change for 24 hours tltereafier. In fact, the patches
`retained more than 50% of their bioadhesive strength alter 72 hours of contact.
`Later, however, adhesion decreased with contact
`time. Scanning electron
`micrographs of milled patches showed a looser structure with increasing
`swelling and a longer soaking time in the buffer solution [22].
`
`B. Characterization of Patch Hydration
`
`For evaluation of the rate of water uptake, the unprotected patch was covered
`by an aqueous medium, and its weight was plotted as a function of time. The
`swelling ratio and initial swelling rate were then calculated. Two degrees of
`acidity were used. Phosphate buffer, pH 7.0 is near the pH of the saliva,
`whereas phosphate buffer, pH 2.6 approximates the conditions created around
`the patch on the gingiva by the ionization of the PAA. There was a striking
`difference in the extent of hydration as a function of pH (Figure 5). At pH
`2.6, the extent of hydration afier 10 hours was approximately 200%, whereas
`24
`
`22
`N O
`..
`
`
`
`Ratioofhydratedpatchweight
`weightoNInanon3:3I37on
`todrypatch
`
`10
`
`15
`
`20
`
`25
`
`Tune (hours)
`
`Rate of uptake of water into PAAIPIBIPIP patches at pH 2.6 and 7.0.
`
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`
`DeGrande et ml
`
`at pH 7.0, this value was l000°/o. The extent of hydration at pH 7.0 is unlikely
`to be so high in the in vivo situation.
`The extent of patch hydration also correlated with the PAA concentration:
`the higher the polymer concentration, the greater the hydration. Patch diameter
`and density likewise increased with increasing hydration. The immersion of a
`patch covered by an impermeable backing resulted in less swelling than was
`seen in patches without a backing. In another procedure, patches placed on a
`hydrogel membrane through which they are hydrated likewise became
`hydrated and swelled more slowly.
`
`C. Characterization of Drug Release
`
`Two methods have been used to characterize drug release fi'om patches. One is
`simple dissolution using a modified paddle method. For some formulations,
`special flasks containing 100 mL of the dissolution medium were used. The
`medium, rotation speed,
`time of sampling, and method of analysis were
`adjusted as a function of the formulation. A second method uses a diffusion
`cell for determining drug release and is considered an improvement over
`dissolution in that only one face of the patch is in contact with the medium via
`a hydrated hydrogel, a situation that more closely mimics the moist surface of
`the buccal cavity. For this study, the patch was covered by a protective backing
`and applied to a hydrated hydrogel film (PVPlcellu1ose acetate). The patch
`absorbed medium via the hydrogel,
`then released the drug through the
`hydrogel into the receptor phase.
`In general,
`there was a correlation between drug release and patch
`hydration, suggesting that swelling is an important mechanism. As an example,
`with the dissolution method, buprenorphine was released from the patches in a
`linear fashion over approximately 10 hours; by 24 hours, nearly 75% of the
`drug had been released (Figure 6) [17]. However,
`the microenvironment
`properties of the patch (e.g., pH) might be affected by the interaction between
`the active drug and the polymers,
`implying that the release profile could
`change from drug to drug.
`The efi"ect of patch thickness on drug release was studied with the diffusion
`method, using a fixed weight of melatonin in patches having identical diameters
`(0.5 em‘) but different thicknesses. Melatonin represented 1%, 2%, or 4% of the
`patch weight. As expected, the release rate of melatonin was proportional to its
`concentration in the patch. This in vitro phenomenon has been confirmed
`
`Figure '7. Comparison of rates of release of melatonin from patches of identical
`diameter and drug content but different thickness so that the concentration of melatonin
`is 1%, 2% and 4%.
`
`
`
`Dissolution("/5released)
`
`0 Dissolution
`
`0 Water uptake
`
`‘ID
`
`)0
`
`Ln
`
`Time (hours)
`
`
`
`
`
`I°M/("M-‘MOIwield“1319M
`
`Figure 6. Dissolution (O) and swelling (0) profiles of buccal
`buprenorphine.
`
`patches containing
`
`°/eReleased
`
`‘Ir 1% melatonin
`O 2%rneIa.t.0nirl
`A 4% melatonin
`
`10
`
`15
`
`Time (hours)
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`296
`
`Decrande et II
`
`Patches
`
`in vivo (Section VI.B.1). The profile and total extent of release suggest the
`establishment of a concentration gradient within the patch (Figure 7).
`~
`
`iv. nv vrvo AND PRECLINICAL sronms
`
`A. Animal Models and Testing Methods
`
`D. Additional Studies and Discussion
`
`The effects of the two patch manufacturing processes on the properties of
`patches containing melatonin were compared. The maximum detachment
`forces were similar, but the release of melatonin was faster from patches made
`by the solvent cast processthan ti-om milled patches. This effect of the
`manufactining process was also reflected in the faster hydration of the former
`type of patch, probably because of a looser structure.
`Patches with a high PAA content and high PIBIPIP ratio have low surface
`energy and water wetting angles. Initially, therefore, one might expect these
`patches to be more adhesive. However, we were unable to predict the adhesion
`of buccal patches on the basis of their surface properties alone. Because the
`wetting angle and surface energy indicate only the
`ability of a patch to
`adhere to a substrate, the relation between bioadhesion and the morphologic
`structure of the patches must be considered [17].
`Adhesion increased during the first few hours of contact with the test
`medium, an observation that may reflect increasing interpenetration of the
`macromolecular chains at the polymer-polymer interface [23]. Jabbari et al
`[24],
`using
`the
`technique
`of
`attenuated
`total
`reflection
`infrared
`spectrophotometry, found that chain interpenetration is indeed important in the
`bioadhesion of PAA at a mucin interface, as the mucin swells the crosslinked
`PAA matrix. The later decrease in adhesion can then be explained by the
`relaxation of PAA, as shown by electron microscopy. However, considerable
`bioadliesive strength was still present in the patches after 24 hours, indicating
`that the patches would provide sufficient mucosal adhesion to permit once
`daily administration.
`The release profile for buprenorphine from the TMD patch was similar to
`that reported for lidocaine in buccal patches containing 30 mg of a freeze dried
`1:2 mixture of hydroxypropyl cellulose and PAA [25]. The curve obtained
`with the current patches (see Figure 6) suggests a sustained delivery of
`buprenorphine over a 24 hour period, with the ultimate release of nearly 75%
`of the drug. The correlation between drug release and water uptake curves also
`suggests that patch swelling is the principal determinant of buprenorphine
`release.
`
`these studies suggest that the strength and duration of
`In summary,
`adhesion and the rate of drug release can all be controlled by manipulating the
`PAA:elastomer ratio and that patches composed of these materials have the
`physical properties necessary for controlled buccal delivery of a variety of
`drugs.
`
`E"°“ Sm?“ Changes in thenature or the ratio of components in a mucoadhesive
`drug delivery system or in the method of manufacture can have a profound
`efifect on the extent of delivery of drug in vivo as well as in vitro [12]
`Therefore, it is necessary to refine patch designs by in vivo testing to select:
`formulations suitable for clinical trials.
`
`Considerable effort has been devoted to the identification of an animal
`model that reflects the behavior of human buccal epithelium [25 26]. This
`topic has been discussed in detail in Chapters 1 and 7. We have relied on two
`models, the rat with a ligated esophagus and the Beagle dog, as our primary in
`‘W0 5°"°°n“1E Systems. The rat model is usefiil in the earliest development of
`drugs such as LMW heparin for which transmucosal delivery is problematic
`because of molecular weight and other factors. Because the animal is small
`even modest amounts of drug absorption can be detected by assay of the
`plasma. The same feature makes the rat a good screening tool for promoters of
`drug absorption. This model allows one to answer the question, “can this drug,
`in any formulation, be observed to cross a mucosal membrane?” If not, there
`would seem to be little point in putting it into a patch.
`The Beagle dog is useful in that it is a relatively large and docile animal
`that is tolerant of frequent handling and oral manipulation. Moreover, repeated
`blood samples can obtained easily. Most important, its oral mucosa tissue is
`generally nonkeratinized and essentially lipoidal, like that of the human, and
`the tissues of the two species have nearly equivalent permeabilities for a large
`number of compounds. Several drugs that have low bioavailability after oral
`administration to humans. or dogs, such as nitroglycerin [27], flurbiprofen [23],
`m—°M1_1I1_ and other peptides
`[29, 39]. and opiates
`[31, 32], have been
`administered buccally to the dog with encouraging results. Moreover,
`the
`diu-ation of adhesion and extent ofpatch hydration on the dog oral mucosa are
`good [63].
`In
`
`B. Results of Initial Studies of TMD Patch in Dogs
`
`1.
`
`Tolerance
`
`Daily application of a placebo patch for 14 hours on six sites on the upper gum
`over a 4 week period induced only slight inflammatory reactions detectable by
`microscopic examination. No macroscopic change in the oral cavity was noted,
`At the end of the observation period, total reversal of the inflammatory
`
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`298
`
`DeGrande et al
`
`Patches
`
`Tm patches Placed on gum. Eslradiol 1.0% wm
`
`.4 CCO
`
`_ OD
`
`
`
`
`
`PlasmaLevels.pgimt
`
`(3)
`
`0246 s1o12141e1s2o22242s2a3o
`Time, Hours
`
`18 Two patches placed on gum.
`T013‘ drug Cooler“: 75 ""3
`
`patches removed
`._—
`
`_E‘-
`ca0
`
`E 1
`
`5on>
`to
`_i
`to
`EU}
`E0.
`
`0 2 4 6 B101214161B202224262B30
`
`(b)
`
`Time, Hours
`
`Figure 8. Examples of drug delivery to dogs fi-om TMD patches; (3) est,-adioli (3,)
`theophylline.
`
`‘
`water soluble dye was monitored under ultraviolet light alter patch application
`to the gingiva or lip of Beagle dogs. In animals receiving patches without the
`occlusive backing, fluoiescein could be detected outside the patch within
`approximately 30 minutes. The dye spread rapidly throughout the ma] cavity
`so that alter 1 to 2 hours, most of the inside of the animal’s mouth on the Sid;
`of the patch demonstrated fluorescence, and by 5 hours, the patch was showing
`signs of dye depletion. In contrast, patches with an occlusive backing permitted
`only a gradual circumferential spread of fluorescein, such that by 8 hours afiet
`application, the zone of difliision was approximately twice the diameter of the
`Piltcll Thesfl results suggest that swallowing of dye leached by saliva from the
`
`TEVA EXHIBIT 1027
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`‘"” = ~
`_
`.
`,. v.v-u-V-.-u¢s:-q-.»§--.--.--....g4.._
`
`reaction was found. No additional reaction was observed hi animals receiving a
`1 mg melatonin patch instead of a placebo.
`
`2.
`
`Biauvattability
`
`A variety of model pharmaceutical compounds were chosen for preliminary
`testing which represented a large range of molecular weights (180-4000 Da)
`and water solubilities. The results of these preliminary determinations are
`shown in Table 1. Typical plasma concentration profiles of some of the drugs
`that demonstrated good bioavailability from buccal patches are depicted in
`Figureli.
`
`3. Avoidance oforal delivery
`
`Drug in a buccal patch may diffuse directly into the saliva and be swallowed; if
`the drug in question is destroyed in the stomach, this portion of the dose will
`be lost. To investigate this possibility, buccal patches containing fluorescein
`were prepared with and without a protective backing, and the diffusion of the
`
`Table 1. Compounds Screened for Buccal Patch Delivery in the Beagle Dog.
`
`Compound
`
`MW
`
`Solubility
`in water
`
`Oral
`bioavailability
`
`Theophylline
`Propranolol
`Nitroglycerin
`Digoxin
`Imiquimod
`
`Estradiol
`Morphine
`
`Buprenorphine
`
`468
`
`Melatonin
`LMW Heparin
`'1:,-ee base
`
`232
`~ 4000
`
`High
`Variable
`Low
`Variable
`Low
`
`Very low
`Variable
`
`1 gll20 rnL
`High
`Low
`Low
`FB‘: insoluble
`HCI: high
`Low
`FE‘: insoluble
`HC1: 1 g] 15 I111.
`S04: 1 gm‘ ml.
`KB“: insoluble
`HC1: moderate
`Moderate
`Moderate
`
`Buccal
`bioavail-
`ability
`
`Moderate
`Poor
`High
`High
`None
`Moderate
`High
`Moderate
`
`High
`High
`High
`High
`
`h
`
`'
`
`‘
`
`_
`
`_
`
`'
`
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`

`

`300
`
`DeGrande et al
`
`Patches
`
`occlusive backed patch was not likely to have been a significant contributor to
`plasma concentration. Conversely, these results demonstrate the potential for
`local oral delivery from an unoccluded patch.
`
`V. TOLERANCE AN