Editor: Donna Balado
`
`Managing Editor: Jennifer Schmidt
`Marketing Manager: Christine Kushner
`
`Copyright © 1999 Lippincott Wflliams & Willdns
`
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`
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`mation storage and retrieval systemwithout written permission from the copyright owner.
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`The publisher is not responsible (as a matter of product liability, negligence, or otherwise)
`for any injury resulting from any material contained herein. This publication contains in-
`formation relating to general principles of medical care which should not be construed as
`specific instructions for individual patients. Manufacturers’product information and pack-
`age inserts should be reviewed for current information, including contraindications,
`dosages, and precautions.
`
`Printed in the United States ofAmerica
`
`Library of Congress Cata1oging-in-Publication Data
`
`Ansel, Howard C., 1933-
`Pharmaceutical dosage forms and drug delievery systems / Howard C.
`Ansel, LoydV. Allen, Jr., Nicholas G. Popovich. —— 7th ed.
`p.
`cm.
`Includes bibliographical references and index.
`ISBN 0-683-30572-7
`2. Drug delivery systems.
`1. Drugs—-Dosage forms.
`II. Popovich, Nicholas G.
`III. Title.
`[DNLM: 1. Dosage Forms.
`2. Drug Delivery Systems. QV 785 A618i 1999]
`RS200.A57
`1999
`615’.1—dc21
`DNLM/DLC
`for Library of Congress
`
`1. Allen, LoydV.
`
`99-17498
`CH’
`
`The publishers have made every eflort to trace the copyright holders for borrowed material. Ifthey
`have inadvertently overlooked any, they will be pleased to make the necessary arrangements at
`the first opportunity.
`-
`
`The use of portions of the text of USP23/NF18, copyright 1994, is by permission of the USP
`Convention, Inc. The Convention is not responsible for any inaccuracy of quotation or for
`any false or misleading implication that may arise from separation of excerpts from the
`original context or by obsolescence resulting from publication of a supplement.
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`To purchase additional copies of this book call our customer service department at (800)
`638-3030 or fax orders to (301) 824-7390. International customers should call (301)
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`
`99 00 01 02
`1 2 3 4 5 6 7 8 9 10
`
`Astrazeneca Ex. 2102 p. 2
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`

`
`
`
`Contents
`
`Preface
`
`Acknowledgments
`
`Section I. PRINCIPLES OF DOSAGE FORM DESIGN AND DEVELOPMENT
`
`I
`
`2
`
`3
`
`4
`
`5
`
`Introduction to Drugs and Pharmacy
`
`New Drug Development and Approval Process
`
`Dosage Form Design: Pharmaceutic and
`Formulation Considerations
`-
`
`Dosage Form Design: Biopharrnaceutic and
`Pharmacokinetic Considerations
`
`Current Good Manufacturing Practices and Good
`Compounding Practices
`
`Section II. SOLID DOSAGE FORMS AND MODIFIED-RELEASE DRUG DELIVERY SYSTEMS
`
`6
`
`7
`
`8
`
`Powders and Granules
`
`Capsules and Tablets
`
`’
`
`Modified~Release Dosage Forms and Drug Delivery Systems
`
`Section III. SEMI-SOLID AND TRANSDERMAL SYSTEMS
`
`9
`
`I0
`
`Ointments, Creams, and Gels
`
`Transdermal Drug Delivery Systems
`
`v
`
`vii
`
`1
`
`23
`
`60
`
`101
`
`142
`
`164
`
`179
`
`229
`
`_
`
`244
`
`263
`
`ix"
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`

`
`x
`
`Contents
`
`Section IV. PHARMA(EUIICAL INSERIS
`
`II
`
`Suppositories and Inserts
`
`Section V. LIQUID DOSAGE FORMS
`
`I 2
`
`I3
`
`Solutions
`
`Disperse Systems
`
`Section VI. SIERILE DOSAGE FORMS AND DELIVERY SYSTEMS
`
`I 4
`
`Parenterals
`
`I 5
`
`I6
`
`Biologicals
`
`Ophthalmic Solutions and Suspensions
`
`Section VII. NOVEL AND ADVANCED DOSAGE FORMS, DELIVERY SYSTEMS, AND DEVICES
`
`Radiopharmaceuticals
`
`Products of Biotechnology
`
`Novel Dosage Forms and Drug Delivery Technologies
`
`Systems and Techniques of Pharmaceutical Measurement
`
`I 7
`
`I8
`
`I9
`
`Appendix
`
`Index
`
`279
`
`296
`
`346
`
`397
`
`450
`
`469
`
`487
`
`503
`
`535
`
`552
`
`563
`
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`

`
` TRANSDERMAL DRUG
`
`DELIVERY SYSTEMS
`
`
`
`Chapter at a Glance
`
`Factors Affecting Percutaneous Absorption
`Percutaneous Absorption Enhancers
`Chemical Enhancers
`
`lontophoresis and Sonophorasis
`Percutaneous Absorption Models
`In Vivo Studies
`In Vitro Studies
`
`Design Features of Transderrnal Drug
`Delivery Systems (TDDSS)
`Advantages and Disadvantages of TDDSS
`Examples of Transderrnal Drug
`Delivery Systems
`
`Tnmsdermal Scopolamine
`Transdermal Nitroglycerin
`Trrmsdermal Clonfdine
`Trcmsdermel Nicotine
`Tmnsdermal Esfmdfol
`Tnmsdermal Testosterone
`
`Other Trcnsdcrmal Therapeutic Systems
`General Clinical Considerations in the Use
`of TDDSs
`
`TRANSDERMAL DRUG delivery systems (TDDSSJ fa-
`cilitate the passage of therapeutic quantifies of
`drug substances through the skin and into the gen-
`eral circulation for their systemic effects. The con-
`cept for the percutaneous absorption of chug sub-
`stances was first conceived by Stoughtori in 1965
`(1). The first transdermal system, Transdeim Scop
`[Ciba (now Novartis)] was approved by the Food
`and Drug Adrninistration in 1979 for the preven-
`tion of nausea and vomiting associated with travel,
`particularly by sea.
`Evidence of percutaneous drug absorption may
`be found through measurable blood levels of the
`drug, detectable excretion of the clnig andlor its
`metabolites in the urine, and through the clinical
`response of the patient to the administered drug
`therapy. With transderrnal drug delivery, the blood
`concentration needed to achieve therapeutic effi-
`cacy may be determined by comparative analysis of
`patient response to drug blood levels. For transder—
`
`rnal drug delivery, it is considered ideal if the drug
`penetrates through the skin to the underlying blood
`supply without drug buildup in the dermal layers
`(2). This is in direct contrast to the types of topical
`dosage forms discussed in the previous chapter, in
`which dlug residence in the skin, the target organ,
`is desired.
`
`As discussed in the previous chapter, the skin is
`comprised of the stratum corneum (the outer layer),
`the living epidermis, and the dermis, which to-
`gether provide the skirfs barrier layers to penetra-
`tion by external agents (see Fig. 9.6).The film that
`covers the stratum corneum is comprised of sebum
`and sweat, but because of its varied composition
`and lack of continuity it is not a significant factor in
`drug penetration nor are the hair follicles and
`sweat and sebaceous gland ducts which comprise
`only a minor proportion of the skin's surface.
`The percutaneous absorption of a dnig generally
`results from the direct penetration of the drug
`
`263
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`

`
`264
`
`Trrmsdermal Drug Delivery Systems
`
`through the stratum corneum, a 10 to 15 pm thick
`layer of flat, partially desiccated nonliving tissue
`(3-4). The stratum corneum is composed of ap-
`proximately 40% protein (mainly keratin) and 40%
`water, with the balance being lipid, principally as
`triglycerides, free fatty acids, cholesterol, and phos-
`pholipids. The lipid content is concentrated in the
`extracellular phase of the stratum corneum and
`forms to a large extent the membrane surrounding
`the cells. Because a drug's major route of penetra-
`tion is through the intercellular channels, the lipid
`component is considered an important determi-
`nant in the first step of the absorption process (5).
`Once through the stratum corneum, drug mole-
`cules may then pass through the deeper epidermal
`tissues and into the dermis. When the drug reaches
`the vascularized dermal layer, it becomes available
`for absorption into the general circulation.
`The stratum corneum, being keratinized tissue,
`behaves as a semipermeable artificial membrane,
`and drug molecules penetrate by passive diffusion.
`It is the major rate-limiting barrier to transderrnal
`drug transport (6). Over most of the body, the stra-
`tum comeurn has 15-25 layers of flattened con'Leo-
`cytes with an overall thickness of about 10 um (6).
`The rate of drug movement across this skin layer
`depends on the drug concentration in the vehicle,
`its aqueous solubility, and the oil/water partition
`coefficient between the suatum corneum and the
`
`vehicle ('7). Substances that possess both aqueous
`and lipid solubility characteristics are good candi-
`dates for diffusion through the stratum corneum as
`well as through the epidermal and dermal layers.
`
`Factors Affecting
`Percutaneous Absorption
`
`Not all drug substances are suitable for transder—
`rnal drug delivery. Among the factors playing a part
`in percutaneous absorption are the physical and
`chemical properties of the drug, including its mol-
`ecular weight, solubility, partitioning coefficient and
`pKa, the nature of the carrier—vehicle and the con-
`dition of the skin. Although general statements ap-
`plicable to all possible combinations of drug, vehi-
`cle, and skin condition are difficult to draw, the
`consensus of the majority of research findings may
`be summarized as follows (2-11).
`
`1. Drug concentration is an important factor. Gen-
`erally, the amount of drug percutaneously ab-
`sorbed per unit of surface area per time interval
`increases as the concentration of the drug sub-
`stance in the TDDS is increased.
`
`2. More drug is absorbed through percutaneous
`absorption when the drug substance is applied
`to a larger surface area (eg, a larger size TDDS).
`3. The drug substance should have a greaterphysio
`ochernical attraction to the skin than to the vehi-
`
`cle in which it is presented for the drug to leave
`the vehicle in favor of the skin. Some solubility of
`the drug in both lipid and water is thought to be
`essential for effective percutaneous absorption.
`In essence, the aqueous solubility of a drug de-
`termines the concentration presented to the ab-
`sorption site and the partition coefficient influ-
`ences the rate of transport across the absorption
`site. Drugs generally penetrate through the skin
`better in their unionized form. Polar drugs tend
`to cross the cell barrier through the lipid-rich re-
`gions (transcellular route) whereas the nonpolar
`drugs favor transport between cells (intercellular
`route) (6).
`4. Drugs with molecular weights between 100 and
`800 with adequate lipid and aqueous solubility
`can permeate skin. The ideal molecular weight
`of a drug for transdermal drug delivery is be-
`lieved to be 400 or less.
`
`5. The hydration of the skin generally favors per-
`cutaneous absorption. TDDS act as occlusive
`moisture barriers through which the sweat from
`the skin cannot pass, resulting in increased skin
`hydration.
`6. Percutaneous absorption appears to be greater
`when the TDDS is applied to a skin site with a
`thin horny layer than with one that is thick.
`7. Generally, the longer the period of time the
`medicated application is permitted to remain in
`contact with the skin, the greater will be the to-
`tal drug absorption.
`
`These general statements on percutaneous ab-
`sorption apply to skin in the normal state. Skin that is
`abraded or cut will pennit drugs to gain direct access
`to the subcutaneous tissues and the capillary network
`obviating the designed function of the TDDS.
`
`Percutaneous Absorption Enhancers
`
`There is great interest among pharmaceutical
`scientists to develop chernical permeation enhancers
`and physical methods that can increase the percu-
`taneous absorption of therapeutic agents.a
`
`Chemical Enhancers
`
`By definition, a chemical skin penetration en-
`hancer increases skin permeability by reversibly dam-
`
`Astraleneca Ex. 2102 p. 6
`
`

`
`aging or by altering the physicochemical mature of the
`stratum corneum to reduce its dflfusioncl resistance
`(12). Among the alterations are increased hydration
`of the stratum corneum andfor a change in the
`structure of the lipids and lipoproteins in the inter-
`cellular channels through solvent action or denat-
`uralion (4, 13-17).
`Some drugs have an inherent capacity to perme-
`ate the skin without need of chemical enhancers.
`However, in instances in which this is not the case,
`chemical permeation enhancers may be effective in
`rendering an otherwise irnpenauable substance use-
`ful in Iransdermal drug delivery (17). More than 275
`different chemical compounds have been cited in
`the literature as skin penetration enhancers includ-
`ing acetone, azone, dirnethylacetarnide, dlmethyl—
`formamide, dirnethylsulfoxide (DMSO), ethanol,
`oleic acid, polyethylene glycol, propylene glycol and
`sodium lauryl sulfate (13-15) . The selection of a per-
`meation enhancer in developing aTDDS should be
`based not only on its efficacy in enhancing skin per-
`meation, but also on its dennal toxicity (low), and its
`physicochemical and biocompatibility with the sys-
`tems other components (16).
`
`Ioutophoresis and Sonophoresis
`
`In addition to chemical means, there are some
`physical methods being used to enhance trans-
`dermal drug delivery and penetration, namely,
`iontophoresis and sonophoresis (6,15,18—23). Ion-
`tophoresis involves the delivery of charged chemical
`compounds across the skin membrane using an
`applied electrical field. A number of drugs have
`been the subject of such iontophoretic studies,
`including lidocaine (18), dexarnethasone, amino
`acidsfpeptideslirisulin (19-20), verapamil (6), and
`propranolol (21). There is particular interest to de-
`velop alternative routes for the delivery of biologi-
`cally active peptides. These agents are presently
`delivered by injection, because of their rapid Ine-
`tabolism and poor absorption after oral delivery.
`They are also poorly absorbed from the transcler-
`rnal route, because of their large molecular size,
`ionic character and the general impenetrability of
`the skin (20). However, iontophoretic-enhanced
`transdermal delivery has shown some promise as a
`means for peptideiprotein administration.
`Sonoplroresis, or high-frequency ultrasound, is
`also being studied as a means to enhance lII'<':L'f'|.SClEi'—
`rnal drug delivery (22—-23). Among the agents ex-
`amined have been hydrocortisone, lidocaine, and
`salicylic acid in such formulations as gels, creams,
`and lotions. It is thought that hjgh—frequency ultra-
`
`Tmnsdermal Drug Delivery Systems
`
`265
`
`sound can influence the integrity of the stratum
`corneum and thus affect its penetrability.
`
`Percutaneous Absorption Models
`
`Skin permeability and percutaneous absorption
`have been the subject of numerous studies under-
`taken to define the underlying principles and to
`optimize transderrnal drug delivery. Although many
`experimental methods and models have been used,
`they tend to fall into one of two categories: 1) in
`vivo, and 2) in vino studies.
`
`In Vivo Studies
`
`In vivo skin-penetration studies may be under-
`taken for one or more of the following purposes (24):
`
`1. To verify and quantify the cutaneous bioavail-
`ability of a topically applied drug;
`2. To verify and quantify the systemic bioavailabil-
`ity of a transdermally delivered drug;
`3. To establish bioequivalence of different topical
`formulations of the same drug substance;
`4. To determine the incidence and degree of sys-
`temic toxicologic risk following the topical ap-
`plication of a specific dnigtdrug product; and
`5. To relate resultant blood levels of drug in human
`to systemic therapeutic effects.
`
`The most relevant studies are performed in hu-
`mans; however, animal models may be used inso-
`far as they may be effective as predictors of human
`response. Animal models include the weanling pig,
`rhesus Toonlcey, and hairless mouse or rat (24-25).
`Biological samples used in drug penetrationldrug
`absorption studies include skin sections, venous
`blood from the application site, blood from the sys-
`temic circulation and excreta (urine, feces and ex-
`pired air) (24-28).
`
`In Vitro Studies
`
`Skin permeation testing may be performed in
`vitro using various skin tissues (human or animal
`whole sl<'.in, dermis or epidermis) in a diffusion cell
`(29). In vitro penetration studies using human skin
`are limited because of difficulties of procurement,
`storage, expense, and variability in permeation (30).
`Excised animal skins may also be variable in qual-
`ity and permeation. Animal skins are much more
`permeable than human skin. One alternative that
`has been shown to be effective is shed snake skin
`
`(Elaplre obsolete, black rat snake), which is nonliv—
`
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`
`

`
`266
`
`Tnmsdemral Drug Delivery Systems
`
`ing, pure stratum corneum, hairless, and similar to
`human skin, but slightly less permeable (3041).
`Also, the product Living Skin Equivalent (LSE)
`Testskin (Organogenesis, Inc.) was developed as an
`alternative for dermal absorption studies. The ma-
`terial is an organotypic coculture of human dermal
`fibroblasts in a collagen-containing matrix and a
`Stratified epidermis composed of human epidermal
`keratinocytes. The material may be used in cell cul-
`ture studies or in standard diffusion cells.
`
`Diffusion cell systems are employed in vitro to
`quantify the release rates of drugs from topical
`preparations (32), In these systems, skin mem-
`branes or synthetic membranes may be employed
`as barriers to the flow of drug and vehicle, to sim-
`ulate the biologic system. The typical diffusion cell
`has two chambers one on each side of the test dif-
`
`fusion membrane. A temperature—controlled solu-
`tion of the drug to be contained in the TDDS is
`placed in one chamber and a receptor solution in
`the other chamber. When skin is used as the test
`
`membrane, it separates the two solutions. Drug clif-
`tusion through the skin may be determined by per
`iodic sampling and assay of the drug content in the
`receptor solution. The skin may also be analyzed for
`drug content to show drug permeation rates and/or
`drug retention in the skin (29).
`The USP describes the apparatus and procedure
`to determine the drug dissolution (drug release) of
`medication from a transdermai delivery system and
`provides an ”Accepta.nCe Table” against which the
`product must conform to meet the monograph stan-
`dard for a given article (33). Commercial systems are
`available that utilize transdermal diffusion cells and
`
`autosarnplingsystems to determine the release rates
`of drugs from transderrnal systems (34).
`
`Design Features of Transdermal Drug
`Delivery Systems (TDDSs)
`
`Transdermal drug delivery systems (also often
`called transdermal”patches”) are designed to sup-
`port the passage of drug substances from the sur-
`face of the skin, through its various layers and into
`the systemic circulation. Examples of the configu-
`ration and composition ofTDDSs are described in
`the text, presented in Table 10.1 and shown in
`Figures 10.1 through 10.4. Figures 10.5 through
`10.8 depict the manufacture of TDDSs. Technically,
`TDDSs may be categorized into two types, mono-
`lithic and membrane—contro1led systems.
`Monolithic systems incorporate a drug matrix
`layer between backing and frontal layers (Fig. 10-3).
`The drug-matrix layer is composed of a polymeric
`
`material in which the drug is dispersed. The poly-
`mer matrix controls the rate at which the drug is
`released for percutaneous absorption. The matrix
`may be of two types; with or without an excess of
`drug with regard to its equilibrium solubility and
`steady-state concentration gradient at the stratum
`corneum (21,35). In types having no excess, drug is
`available to maintain the saturation of the stratum
`
`corneum only as long as the level of drug in the de-
`vice exceeds the solubility limit of the stratum
`corneum. As the concentration of drug in the de-
`vice diminishes below the skin's saturation limit,
`the transport of drug from device to skin gradually
`declines (35). In systems that have an excess amount
`of drug present in the matrix, a drug reserve is pres-
`ent to assure continued drug saturation at
`the
`stratum comeum. In these instances, the rate of
`drug decline is less than in the type having no drug
`reserve.
`
`In the preparation of monolithic systems, the
`drug and the polymer are dissolved or blended to-
`gether, cast as the matrix and dried (21).The gelled
`matrix may be produced in sheet or cylindrical
`form, with individual dosage units cut and asserti-
`bled between the backing and frontal layers. Most
`TDDSs are designed to contain an excess of drug
`and thus have drug-releasing capacity beyond the
`time frame recommended for replacement. This
`ensures continuous drug availability and absorp-
`tion as used TDDSs are replaced on schedule with
`fresh ones.
`
`Membrane—controlled transderrnal systems are
`designed to contain a drug reservoir or "pouch”,
`usually in liquid or gel form, a rate~controlling
`membrane, and backing, adhesive, and protecting
`layers (Fig. 10—2). 'I‘ransderrn—Nitro (Novartis) and
`Transderm-Scop (Novartis) are examples of this
`technology. Membrane—controllecl systems have the
`advantage over monolithic systems in that as long
`as the drug solution in the reservoir remains
`saturated, the release rate of drug through the con-
`trolling membrane remains constant (21-22). In
`membrane systems, a small quantity of dmg is fre-
`quently placed in the adhesive layer to initiate
`prompt drug absorption and pharrnacotherapeutic
`effects on skin placement. Membrane-controlled
`Systems may be prepared by preconstructlng the
`delivery unit, filling the drug reservoir, and sealing,
`or by a process of lamination, which involves a con-
`tinuous process of constructiomdosing and sealing
`(Figs. 10.5 through 10.8).
`In summary, either the drug delivery device or
`the skin may serve as the rate-controlling mecha-
`nism in drug transport from transderrnal systems.
`
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`
`

`
`Transdermal Drug Delivery Systems
`
`267
`
`
`
`
`
` Therapeutic Agent TDDS Design/Contents Comments
`
`Table 10.1. Examples of Transdermal Drug Delivery Systems (40-44, 47~51}
`
`Clonidone
`Catapres—’ITS
`Four-layered patch: (1) a
`Transdermal therapeutic systems
`(Boelninger Ingelheim)
`backing layer of pigmented
`designed to deliver a therapeutic
`polyester film; (2) drug
`dose of the antihypertensive
`reservoir of clonidine,
`drug clonidine at a constant
`mineral oil, polyisobutylene,
`rate for 7 days, permitting
`and colloidal silicon
`once-a—weel< dosing.TDDS
`dioxide;' (3) a microporous
`generally applied to hairless or
`polypropylene membrane
`shaven areas of upper arm or
`controlling the rate of drug
`torso.
`delivery; and (4) an
`adhesive fonnulation of
`
`Estradiol
`
`Estraderrn (Novartis)
`
`Vivelle (Novartis)
`
`Climara (Berlex)
`
`Fentanyl
`
`Duragesic (lanssenju
`
`agents noted in (2) above.
`
`Four-layered patch: (1) a
`transparent polyester film;
`(2) drug reservoir of estradiol
`and alcohol gelled with
`hydroxypropyl cellulose;
`(3) an ethylene-vinyl acetate
`copolymer membrane; and
`(4) an adhesive formulation
`of light mineral oil and
`polyisobutylene
`
`'['hree—layered patch: (1) a
`translucent ethylene vinyl
`alcohol copolymer film;
`(2) eslxadiol in a matrix of a
`medical adhesive of
`
`polyisobutylene and ethylene
`vinylacetate copolymer; and
`(3) a polyester release liner
`which is removed prior to
`application.
`
`Three—layered system: (1) a
`translucent polyethylene film;
`(2) acrylate adhesive matrix
`containing estradiol; and
`(3) a protective liner of
`siliconized or iluoropolyrner—
`coated polyester film which
`is removed prior to use.
`
`Fourjlayered patch (1) a
`backing layer of polyester
`film; (2) drug reservoir of
`fentanyl and alcohol gelled
`with hydroxyethyl cellulose;
`(3) a rate—cc-ntrolling
`ethylene-vinyl acetate
`copolyrner membrane; and
`(4) a fentanyl-containing
`silicone adhesive.
`
`Transdermal system designed to
`release 17B-estradiol
`continuously. The Iransdermal
`patch is generally applied twice
`weekly over a cycle of 3 weeks
`with dosage frequency adjusted
`as required. The patch is
`generally applied to the trunk
`including the abdomen and
`buttocks, alternating sites with
`each application.
`
`Use and application is similar to
`the Estraderm TDDS.
`
`Use and application similar to the
`Estraderm TDDS. System may
`be applied once weekly.
`
`Transdermal therapeutic system
`providing continuous 72-hour
`systemic delivery of Eentanyl, a
`potent opioid analgesic.'l'he
`drug is indicated in patients
`having chronic pain requiring
`opioid analgesia.
`
`continued
`
`Astraleneca Ex. 2102 p. 9
`
`

`
`Comments
`
`Transdermal therapeutic
`systems providing
`continuous release
`
`and systemic delivery
`of nicotine as an aid
`
`in smoking cessation
`programs.The patches
`listed vary somewhat in
`nicotine content and
`
`dosing schedules.
`
`268
`
`Tmnsdenmtl Drug Delivery Systems
`
`Therapeutic Agent
`Nicotine
`
`Table 10.1. Examples ofTra11sdermal Drug Delivery Systems (40-44, 47-51)
`TDDS
`
`Design/Contents
`
`Habitrol (Novartis
`Consumer)
`
`NicoDerm CQ
`(SmithKline Beecham
`Consumer)
`
`Nicotrol (McNeil
`Consumer)
`
`Prostep (Lederle)
`
`MuIti—Iayered round patch:
`(1) an aluminized backing
`film; (2) a pressure—sensitive
`acrylate adhesive; (3)
`methacryciic acid copolymet
`solution of nicotine dispersed
`in a pad of rioriwoven viscose
`and cotton; (4) an acrylate
`adhesive layer; and (5) a
`protective aluminized release
`liner that overlays the
`adhesive layer and is removed
`prior to use.
`
`Multi-layered rectangular patch:
`(1) an occlusive backing of
`polyethyleneiaiuminuml
`polyesterfethylene-vinyl
`acetate copoiymer; (2) drug
`reservoir of nicotine in an
`ethylene vinyl acetate
`copolymer matrix; (3)
`rate—t:onl.'rolling membrane
`of polyethylene; (4)
`polyisobutylene adhesive;
`and (5) protective liner
`removed prior to application.
`
`Muitiwlayered rectangular patch;
`(1) outer backing of laminated
`polyester film; (2) rate~
`controlling adhesive,
`nonwoven material, and
`nicotine; (3) disposable liner
`removed prior to use.
`
`Multi-layered round patch:
`(1) beige-colored foam tape
`and acrylate adhesive; (2)
`backing foil, gelatin and
`low—density polyethylene
`coating; (3) nicotine-gel
`matrix; (4) protective foil
`with well; and (5) release
`liner removed prior to use.
`
`Nitroglycerin
`
`Deponit (Schwarz Pharma) A three-layer system: (1)
`covering foil; (2) nitroglycerin
`matrix with poiyisobutylent;
`adhesive, plasticizer and
`release membrane; and
`(3) protective foil removed
`before use.
`
`continued
`
`Astrazeneca Ex. 2102 p. 10
`
`

`
`Table 10.1. Examples of Transdermal Drug Delivery Systems (40-44, 47-51)
`TDD5
`Tiierapeutic Agent
`Desigir/Contents
`
`Comments
`
`Trrmsdermal Drug Delivery Systems
`
`269
`
`Nitro—Dur (Key)
`
`Transderm —Nitro
`(Novartis)
`
`Scopolarnine
`
`Transderm Scfip
`(Novartis
`Consumer)
`
`Testosterone
`
`Testoderm (Alza)
`
`Androderrn
`(SInith.Kline
`Beecharn)
`
`Nitroglycerin in a gel—like
`matrix composed of glycerin,
`water, lactose, polyvinyl
`alcohol, povidone and
`sodium citrate sealed in a
`
`polyester-foil—polyethylene
`laminate.
`
`Fou.r—layered patch: (1) backing
`layer of aluminized plastic;
`(2) drug reservoir containing
`rtitroglycerin adsorbed on
`lactose, colloidal silicon
`dioxide, and silicone medical
`fluid, (3) an ethylene/vinyl
`acetate copolymer membrane;
`and {4} silicone adhesive.
`
`Four—laye1'ed patch: (1) backing
`layer of alurninized polyester
`film; (2) drug reservoir of
`scopolamine, mineral oil, and
`polyisobutylene; (3) a
`rnicroporous polypropylene
`membrane for rate delivery of
`scopolamine; and (4) adhesive
`of polyisobutylene, mineral
`oil, and scopoiamine
`
`Three-layer patch: (1) backing
`layer of polyethylene
`terephthalate; (2) matrix film
`layer of testosterone and
`ethylene—vinyl acetate
`copolymer; and (3) adhesive
`strips of polyisobutylene and
`colloidal silicone clloxide.
`
`Five—layer patch: (1) backing
`film of ethylene vinyl acetate
`copolymerlpolyester laminate;
`(2) drug reservoir gel of
`testosterone, alcohol; glycerin,
`glyceryl monooleate, methyl
`laurate gelled with an acrylic
`acid copolymer; (3) a
`rnicroporous polyethylene
`membrane; (4) acrylic adhesive;
`(5) an adhesive polyester
`laminate.
`
`TDDSS designed to provide
`the controlled release of
`nitroglycerin for treatment
`of angina. Daily application
`to chest, upper arm or
`shoulder.
`
`TDDS for continuous release of
`
`scopolamine over a 3-day period
`as required for the prevention of
`nausea and vomiting associated
`with motion sickness. The patch
`is placed behind the ear. When
`repeated administration is
`desired, the first patch is
`removed and the second patch
`placed behind the other ear.
`Also FDA-approved for
`prevention of nausea associated
`with certain anesthetics and
`analgesics used in surgery.
`
`The patch is placed on the scrotum
`in the treatment of testosterone
`
`deficiency.
`
`The patch is placed on the back,
`abdomen, upper arms or thighs
`in the treatment of testosterone
`
`deficiency.
`
`Astrazeneca Ex. 2102 p. 11
`
`

`
`270
`
`Trrmsdermal Drug Delivery Systems
`
`If the drug is delivered to the stratum corneum at a
`rate less than the absorption capacity, the device is
`the controlling factor; if the drug is delivered to the
`skin area to saturation, the skin is the controlling
`
`aaclnmglaw
`Drug ruorbuur
`Mimfiums taruininiw
`rrhomblmu
`Adhnsiuliualmllion
`Shun Sufliel
`
`HI% and
`
`Fig. 10.1 Depiction ofafoimlayeied therapeutic imnsdenmrl
`system showing the mrrtinuous and controlled amount cfmed-
`icai-ion released from the system, penneating the skin and en-
`ter-ing the systemic c-ircrclcztiorz, {Comiesy of/llza Corporzztion.)
`
`factor to the rate of drug absorption. Thus, the rate
`of drug transport in all TDDSS, monolithic and
`membrane, is controlled by either artificial or nat-
`ural (skin) membranes.
`Transderrnal drug delivery systems may be con-
`structed of a number of layers, including 1) an oc-
`clusive backing membrane to protect the system
`from environrnental entry and from loss of drug
`from the system 01' rnoistllre from the skin; 2) a
`drug reservoir or matrix system to store and release
`the drug at the skin—site; 3) a release liner, which is
`removed before application and enables drug re-
`lease; and 4) an adhesive layer to maintain Contact
`with the skin after application. TDDS5 are pack-
`aged in individual sealed packets to preserve and
`protect them until use.
`The backing layer must be occlusive to retain
`skin moisture and hydrate the site of application
`
`backing
`
`drug reservoir
`
`
`
`control membrane
`
`adhesive layer
`
`protective peel strip
`
`Fig. 10.2 The Transderm—Nitro Tiansdermcl Therapeutic System (Summit) The patch delivers nitroglycerin through the skin
`directly into the blood stream for 24 hours. Transderm-Nitra is used to treat and prevent engine. The system consists ofa water-
`resistant backing layer, it resenmir of nitroglycerin, fialloweci by a semipermeable memhmrte to comtml precisely and predictably the
`release ofmerlicine, and an adhesive layer to hold the system onto the skin. The adhesive layer also corrtains an initial priming dose
`ofnil.'roglycerin to insure prompt release and absorption ofthe medfcalion. (Courtesy cfsummii‘ Pharmaceuticals .fNovari'r's]).
`
` 1 FOIL CCNERSTRIP
`
`2 EHUG MATRIX
`1 RELEISE IJNEFI
`I FOII. I-'<SEPU«l'E
`
`
`
`
`
`
`5. Jpggfl POROUS
`E. JESOHEENT PAD
`7 DCCLUBIUE ouenuw
`
`Fig. 10.3 Nii?‘o—DurTransdermal Infusion Sysiem, depfi./flag the construction ofthe product. (Courtesy ofKeyPhcmnaceuticels, Inc.)
`
`AstraZeneca Ex. 2102 p. 12
`
`

`
`Trcmsdermal Drug Delivery Systems
`
`271
`
`(1) Film Backing
`
`(2) Drugmdhesive Layer
`
`(3) Protective Liner
`
`2:1
`
`Fig. 10.4 Depiction ofa two-layered mmsdenmzl drug delivery system, excluding the protective liner which is removed prior to
`application.
`
`enabling increased drug penetration. Preferred back-
`ing materials are approximately 2-3 nun in thick-
`ness and have a low moisture vapor transmission
`rate of approximately <20 g/1n2l24 hr (36). Films of
`polypropylene, polyethylene, and polyolefin which
`are transparent or pigmented are in use in TDDSs
`as backing liners.
`The adhesive layer must be pressure sensitive,
`providing the ability to adhere to the skin with
`minimal pressure and remain in place for the in-
`tended period of wear. The adhesive should be
`nomirritating, allow easy peel-off after use, permit
`unirnpeded drug flux to the skin and must be com-
`patible with all other system components. The ad-
`hesive material is usually safety tested for skin
`compatibility including tests for skin irritation, skin
`sensitivity and cytotoxicity (37). in some 'l‘DDSs,
`:l.'l'1€ drug is contained within the adhesive layer.
`Polybutylacrylate is commonly used as the adhe-
`sive in TDDS3.
`
`The drug release membranes are commonly made
`of polyethylene, with microporous structures of
`varying pore sizes to fit the desired specifications of
`the particular transderrnal system.
`Included among the design objectives of TDDSS
`are the following (2,8,35,38—39).AT'DDS should do
`the following:
`
`1. Deliver the drug at an optimal rate to the skin for
`percutaneous absorption at therapeutic levels;
`2. Contain medicinal agents having the neces-
`sary physicochemical characteristics to release
`from the system and paltition into the stratum
`corneurn;
`
`3. Occlude the skin to ensure the one-way flux of
`the drug into the stratum corneum;
`4. Have a therapeutic advantage over other dosage
`forms and drug delivery systems;
`5. Have components as adhesive, vehicle, and ac-
`tive agent which are not irritating or sensitizing
`to the skin; and
`6. Adhere well to the patient’s skin and have a
`patch-size, appearance, and site-placement that
`encourages patient acceptance.
`
`Fig. 10.5 Pilot scale manufacture of transdermal patches.
`(Courtesy afElan Corporation, pic.)
`
`Advantages and
`Disadvantag